<?xml version="1.0" encoding="us-ascii"?>
<!-- DFS ActiveDisclosure(SM) XBRL Linkbase Document - http://www.dfsco.com/financial-services/ -->
<!-- Creation Date      : 2019-03-14T21:09:06.6128203+00:00 -->
<!-- Version            : 3.3.6989.14284 -->
<!-- Package ID         : 2f20dd7522a24ea58e96fa5e90bc9e1d -->
<!-- Copyright (c) 2019 Donnelley Financial, LLC. All Rights Reserved. -->
<linkbase xmlns="http://www.xbrl.org/2003/linkbase" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:xbrldt="http://xbrl.org/2005/xbrldt" xsi:schemaLocation="http://www.xbrl.org/2003/linkbase http://www.xbrl.org/2003/xbrl-linkbase-2003-12-31.xsd">
  <arcroleRef xlink:type="simple" xlink:href="http://www.xbrl.org/2005/xbrldt-2005.xsd#all" arcroleURI="http://xbrl.org/int/dim/arcrole/all" />
  <arcroleRef xlink:type="simple" xlink:href="http://www.xbrl.org/2005/xbrldt-2005.xsd#dimension-default" arcroleURI="http://xbrl.org/int/dim/arcrole/dimension-default" />
  <arcroleRef xlink:type="simple" xlink:href="http://www.xbrl.org/2005/xbrldt-2005.xsd#dimension-domain" arcroleURI="http://xbrl.org/int/dim/arcrole/dimension-domain" />
  <arcroleRef xlink:type="simple" xlink:href="http://www.xbrl.org/2005/xbrldt-2005.xsd#domain-member" arcroleURI="http://xbrl.org/int/dim/arcrole/domain-member" />
  <arcroleRef xlink:type="simple" xlink:href="http://www.xbrl.org/2005/xbrldt-2005.xsd#hypercube-dimension" arcroleURI="http://xbrl.org/int/dim/arcrole/hypercube-dimension" />
  <roleRef xlink:type="simple" xlink:href="zfgn-20181231.xsd#TemplateLink" roleURI="http://www.zafgen.com/20181231/role/TemplateLink" />
  <roleRef roleURI="http://www.zafgen.com/20181231/taxonomy/role/StatementConsolidatedStatementsOfChangesInStockholdersEquity" xlink:href="zfgn-20181231.xsd#Role_StatementConsolidatedStatementsOfChangesInStockholdersEquity" xlink:type="simple" />
  <definitionLink xlink:type="extended" xlink:role="http://www.zafgen.com/20181231/taxonomy/role/StatementConsolidatedStatementsOfChangesInStockholdersEquity">
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_NetIncomeLoss" xlink:type="locator" xlink:label="us-gaap_NetIncomeLoss" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_MarketableSecuritiesUnrealizedGainLoss" xlink:type="locator" xlink:label="us-gaap_MarketableSecuritiesUnrealizedGainLoss" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_AdjustmentsToAdditionalPaidInCapitalSharebasedCompensationRequisiteServicePeriodRecognitionValue" xlink:type="locator" xlink:label="us-gaap_AdjustmentsToAdditionalPaidInCapitalSharebasedCompensationRequisiteServicePeriodRecognitionValue" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_StockIssuedDuringPeriodSharesRestrictedStockAwardNetOfForfeitures" xlink:type="locator" xlink:label="us-gaap_StockIssuedDuringPeriodSharesRestrictedStockAwardNetOfForfeitures" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_StockIssuedDuringPeriodValueRestrictedStockAwardNetOfForfeitures" xlink:type="locator" xlink:label="us-gaap_StockIssuedDuringPeriodValueRestrictedStockAwardNetOfForfeitures" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_StockIssuedDuringPeriodSharesNewIssues" xlink:type="locator" xlink:label="us-gaap_StockIssuedDuringPeriodSharesNewIssues" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_StockIssuedDuringPeriodValueNewIssues" xlink:type="locator" xlink:label="us-gaap_StockIssuedDuringPeriodValueNewIssues" />
    <loc xlink:href="zfgn-20181231.xsd#zfgn_StockIssuedDuringPeriodSharesStockOptionsExercisedAndEmployeeStockPurchasePlans" xlink:type="locator" xlink:label="zfgn_StockIssuedDuringPeriodSharesStockOptionsExercisedAndEmployeeStockPurchasePlans" />
    <loc xlink:href="zfgn-20181231.xsd#zfgn_StockIssuedDuringPeriodValueStockOptionsExercisedAndEmployeeStockPurchasePlan" xlink:type="locator" xlink:label="zfgn_StockIssuedDuringPeriodValueStockOptionsExercisedAndEmployeeStockPurchasePlan" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_SharesOutstanding" xlink:type="locator" xlink:label="us-gaap_SharesOutstanding" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_StockholdersEquity" xlink:type="locator" xlink:label="us-gaap_StockholdersEquity" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_AccumulatedOtherComprehensiveIncomeMember" xlink:type="locator" xlink:label="us-gaap_AccumulatedOtherComprehensiveIncomeMember" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_RetainedEarningsMember" xlink:type="locator" xlink:label="us-gaap_RetainedEarningsMember" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_AdditionalPaidInCapitalMember" xlink:type="locator" xlink:label="us-gaap_AdditionalPaidInCapitalMember" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_CommonStockMember" xlink:type="locator" xlink:label="us-gaap_CommonStockMember" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_EquityComponentDomain" xlink:type="locator" xlink:label="us-gaap_EquityComponentDomain" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_EquityComponentDomain" xlink:type="locator" xlink:label="us-gaap_EquityComponentDomain_2" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_StatementEquityComponentsAxis" xlink:type="locator" xlink:label="us-gaap_StatementEquityComponentsAxis" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_StatementTable" xlink:type="locator" xlink:label="us-gaap_StatementTable" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_StatementLineItems" xlink:type="locator" xlink:label="us-gaap_StatementLineItems" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/all" xlink:from="us-gaap_StatementLineItems" xlink:to="us-gaap_StatementTable" order="10010.00" priority="2" use="optional" xbrldt:contextElement="segment" xbrldt:closed="true" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="us-gaap_StatementTable" xlink:to="us-gaap_StatementEquityComponentsAxis" order="10040.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="us-gaap_StatementEquityComponentsAxis" xlink:to="us-gaap_EquityComponentDomain_2" order="10050.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="us-gaap_StatementEquityComponentsAxis" xlink:to="us-gaap_EquityComponentDomain" order="10070.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_EquityComponentDomain" xlink:to="us-gaap_CommonStockMember" order="10090.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_EquityComponentDomain" xlink:to="us-gaap_AdditionalPaidInCapitalMember" order="10130.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_EquityComponentDomain" xlink:to="us-gaap_RetainedEarningsMember" order="10150.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_EquityComponentDomain" xlink:to="us-gaap_AccumulatedOtherComprehensiveIncomeMember" order="10170.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_StatementLineItems" xlink:to="us-gaap_StockholdersEquity" order="10200.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_StatementLineItems" xlink:to="us-gaap_SharesOutstanding" order="10220.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_StatementLineItems" xlink:to="zfgn_StockIssuedDuringPeriodValueStockOptionsExercisedAndEmployeeStockPurchasePlan" order="10340.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_StatementLineItems" xlink:to="zfgn_StockIssuedDuringPeriodSharesStockOptionsExercisedAndEmployeeStockPurchasePlans" order="10360.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_StatementLineItems" xlink:to="us-gaap_StockIssuedDuringPeriodValueNewIssues" order="10480.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_StatementLineItems" xlink:to="us-gaap_StockIssuedDuringPeriodSharesNewIssues" order="10500.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_StatementLineItems" xlink:to="us-gaap_StockIssuedDuringPeriodValueRestrictedStockAwardNetOfForfeitures" order="10620.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_StatementLineItems" xlink:to="us-gaap_StockIssuedDuringPeriodSharesRestrictedStockAwardNetOfForfeitures" order="10640.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_StatementLineItems" xlink:to="us-gaap_AdjustmentsToAdditionalPaidInCapitalSharebasedCompensationRequisiteServicePeriodRecognitionValue" order="10760.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_StatementLineItems" xlink:to="us-gaap_MarketableSecuritiesUnrealizedGainLoss" order="10900.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_StatementLineItems" xlink:to="us-gaap_NetIncomeLoss" order="11040.00" priority="2" use="optional" />
  </definitionLink>
  <roleRef roleURI="http://www.zafgen.com/20181231/taxonomy/role/DisclosureStockBasedAwardsTables" xlink:href="zfgn-20181231.xsd#Role_DisclosureStockBasedAwardsTables" xlink:type="simple" />
  <definitionLink xlink:type="extended" xlink:role="http://www.zafgen.com/20181231/taxonomy/role/DisclosureStockBasedAwardsTables">
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_ScheduleOfEmployeeServiceShareBasedCompensationAllocationOfRecognizedPeriodCostsTextBlock" xlink:type="locator" xlink:label="us-gaap_ScheduleOfEmployeeServiceShareBasedCompensationAllocationOfRecognizedPeriodCostsTextBlock" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_ScheduleOfShareBasedCompensationStockOptionsActivityTableTextBlock" xlink:type="locator" xlink:label="us-gaap_ScheduleOfShareBasedCompensationStockOptionsActivityTableTextBlock" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_ScheduleOfShareBasedPaymentAwardStockOptionsValuationAssumptionsTableTextBlock" xlink:type="locator" xlink:label="us-gaap_ScheduleOfShareBasedPaymentAwardStockOptionsValuationAssumptionsTableTextBlock" />
    <loc xlink:href="zfgn-20181231.xsd#zfgn_MarketBasedVestingConditionsMember" xlink:type="locator" xlink:label="zfgn_MarketBasedVestingConditionsMember" />
    <loc xlink:href="zfgn-20181231.xsd#zfgn_TimeBasedVestingMember" xlink:type="locator" xlink:label="zfgn_TimeBasedVestingMember" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_ShareBasedCompensationArrangementsByShareBasedPaymentAwardAwardTypeAndPlanNameDomain" xlink:type="locator" xlink:label="us-gaap_ShareBasedCompensationArrangementsByShareBasedPaymentAwardAwardTypeAndPlanNameDomain" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_ShareBasedCompensationArrangementsByShareBasedPaymentAwardAwardTypeAndPlanNameDomain" xlink:type="locator" xlink:label="us-gaap_ShareBasedCompensationArrangementsByShareBasedPaymentAwardAwardTypeAndPlanNameDomain_2" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_AwardTypeAxis" xlink:type="locator" xlink:label="us-gaap_AwardTypeAxis" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_StatementTable" xlink:type="locator" xlink:label="us-gaap_StatementTable" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_StatementLineItems" xlink:type="locator" xlink:label="us-gaap_StatementLineItems" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/all" xlink:from="us-gaap_StatementLineItems" xlink:to="us-gaap_StatementTable" order="10010.00" priority="2" use="optional" xbrldt:contextElement="segment" xbrldt:closed="true" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="us-gaap_StatementTable" xlink:to="us-gaap_AwardTypeAxis" order="10040.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="us-gaap_AwardTypeAxis" xlink:to="us-gaap_ShareBasedCompensationArrangementsByShareBasedPaymentAwardAwardTypeAndPlanNameDomain_2" order="10050.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="us-gaap_AwardTypeAxis" xlink:to="us-gaap_ShareBasedCompensationArrangementsByShareBasedPaymentAwardAwardTypeAndPlanNameDomain" order="10070.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ShareBasedCompensationArrangementsByShareBasedPaymentAwardAwardTypeAndPlanNameDomain" xlink:to="zfgn_TimeBasedVestingMember" order="10090.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ShareBasedCompensationArrangementsByShareBasedPaymentAwardAwardTypeAndPlanNameDomain" xlink:to="zfgn_MarketBasedVestingConditionsMember" order="10210.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_StatementLineItems" xlink:to="us-gaap_ScheduleOfShareBasedPaymentAwardStockOptionsValuationAssumptionsTableTextBlock" order="10240.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_StatementLineItems" xlink:to="us-gaap_ScheduleOfShareBasedCompensationStockOptionsActivityTableTextBlock" order="10320.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_StatementLineItems" xlink:to="us-gaap_ScheduleOfEmployeeServiceShareBasedCompensationAllocationOfRecognizedPeriodCostsTextBlock" order="10420.00" priority="2" use="optional" />
  </definitionLink>
  <roleRef roleURI="http://www.zafgen.com/20181231/taxonomy/role/DisclosureNatureOfBusinessAndBasisOfPresentationAdditionalInformationDetail" xlink:href="zfgn-20181231.xsd#Role_DisclosureNatureOfBusinessAndBasisOfPresentationAdditionalInformationDetail" xlink:type="simple" />
  <definitionLink xlink:type="extended" xlink:role="http://www.zafgen.com/20181231/taxonomy/role/DisclosureNatureOfBusinessAndBasisOfPresentationAdditionalInformationDetail">
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_CashCashEquivalentsAndShortTermInvestments" xlink:type="locator" xlink:label="us-gaap_CashCashEquivalentsAndShortTermInvestments" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_RestrictedCashAndInvestments" xlink:type="locator" xlink:label="us-gaap_RestrictedCashAndInvestments" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_DebtInstrumentFaceAmount" xlink:type="locator" xlink:label="us-gaap_DebtInstrumentFaceAmount" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_ProceedsFromIssuanceInitialPublicOffering" xlink:type="locator" xlink:label="us-gaap_ProceedsFromIssuanceInitialPublicOffering" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_SharesIssuedPricePerShare" xlink:type="locator" xlink:label="us-gaap_SharesIssuedPricePerShare" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_StockIssuedDuringPeriodSharesNewIssues" xlink:type="locator" xlink:label="us-gaap_StockIssuedDuringPeriodSharesNewIssues" />
    <loc xlink:href="zfgn-20181231.xsd#zfgn_NetProceedsFromSaleOfSecurities" xlink:type="locator" xlink:label="zfgn_NetProceedsFromSaleOfSecurities" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_RetainedEarningsAccumulatedDeficit" xlink:type="locator" xlink:label="us-gaap_RetainedEarningsAccumulatedDeficit" />
    <loc xlink:href="https://xbrl.sec.gov/dei/2018/dei-2018-01-31.xsd#dei_EntityIncorporationDateOfIncorporation" xlink:type="locator" xlink:label="dei_EntityIncorporationDateOfIncorporation" />
    <loc xlink:href="zfgn-20181231.xsd#zfgn_TermLoanMember" xlink:type="locator" xlink:label="zfgn_TermLoanMember" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_LongtermDebtTypeDomain" xlink:type="locator" xlink:label="us-gaap_LongtermDebtTypeDomain" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_LongtermDebtTypeDomain" xlink:type="locator" xlink:label="us-gaap_LongtermDebtTypeDomain_2" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_LongtermDebtTypeAxis" xlink:type="locator" xlink:label="us-gaap_LongtermDebtTypeAxis" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_IPOMember" xlink:type="locator" xlink:label="us-gaap_IPOMember" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_SaleOfStockNameOfTransactionDomain" xlink:type="locator" xlink:label="us-gaap_SaleOfStockNameOfTransactionDomain" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_SaleOfStockNameOfTransactionDomain" xlink:type="locator" xlink:label="us-gaap_SaleOfStockNameOfTransactionDomain_2" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_SubsidiarySaleOfStockAxis" xlink:type="locator" xlink:label="us-gaap_SubsidiarySaleOfStockAxis" />
    <loc xlink:href="zfgn-20181231.xsd#zfgn_OrganizationConsolidationAndPresentationOfFinancialStatementsDisclosureTable" xlink:type="locator" xlink:label="zfgn_OrganizationConsolidationAndPresentationOfFinancialStatementsDisclosureTable" />
    <loc xlink:href="zfgn-20181231.xsd#zfgn_OrganizationConsolidationAndPresentationOfFinancialStatementsDisclosureLineItems" xlink:type="locator" xlink:label="zfgn_OrganizationConsolidationAndPresentationOfFinancialStatementsDisclosureLineItems" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/all" xlink:from="zfgn_OrganizationConsolidationAndPresentationOfFinancialStatementsDisclosureLineItems" xlink:to="zfgn_OrganizationConsolidationAndPresentationOfFinancialStatementsDisclosureTable" order="10010.00" priority="2" use="optional" xbrldt:contextElement="segment" xbrldt:closed="true" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="zfgn_OrganizationConsolidationAndPresentationOfFinancialStatementsDisclosureTable" xlink:to="us-gaap_SubsidiarySaleOfStockAxis" order="10040.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="us-gaap_SubsidiarySaleOfStockAxis" xlink:to="us-gaap_SaleOfStockNameOfTransactionDomain_2" order="10050.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="us-gaap_SubsidiarySaleOfStockAxis" xlink:to="us-gaap_SaleOfStockNameOfTransactionDomain" order="10070.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_SaleOfStockNameOfTransactionDomain" xlink:to="us-gaap_IPOMember" order="10090.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="zfgn_OrganizationConsolidationAndPresentationOfFinancialStatementsDisclosureTable" xlink:to="us-gaap_LongtermDebtTypeAxis" order="10140.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="us-gaap_LongtermDebtTypeAxis" xlink:to="us-gaap_LongtermDebtTypeDomain_2" order="10150.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="us-gaap_LongtermDebtTypeAxis" xlink:to="us-gaap_LongtermDebtTypeDomain" order="10170.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_LongtermDebtTypeDomain" xlink:to="zfgn_TermLoanMember" order="10190.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="zfgn_OrganizationConsolidationAndPresentationOfFinancialStatementsDisclosureLineItems" xlink:to="dei_EntityIncorporationDateOfIncorporation" order="10240.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="zfgn_OrganizationConsolidationAndPresentationOfFinancialStatementsDisclosureLineItems" xlink:to="us-gaap_RetainedEarningsAccumulatedDeficit" order="10290.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="zfgn_OrganizationConsolidationAndPresentationOfFinancialStatementsDisclosureLineItems" xlink:to="zfgn_NetProceedsFromSaleOfSecurities" order="10350.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="zfgn_OrganizationConsolidationAndPresentationOfFinancialStatementsDisclosureLineItems" xlink:to="us-gaap_StockIssuedDuringPeriodSharesNewIssues" order="10410.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="zfgn_OrganizationConsolidationAndPresentationOfFinancialStatementsDisclosureLineItems" xlink:to="us-gaap_SharesIssuedPricePerShare" order="10470.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="zfgn_OrganizationConsolidationAndPresentationOfFinancialStatementsDisclosureLineItems" xlink:to="us-gaap_ProceedsFromIssuanceInitialPublicOffering" order="10530.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="zfgn_OrganizationConsolidationAndPresentationOfFinancialStatementsDisclosureLineItems" xlink:to="us-gaap_DebtInstrumentFaceAmount" order="10590.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="zfgn_OrganizationConsolidationAndPresentationOfFinancialStatementsDisclosureLineItems" xlink:to="us-gaap_RestrictedCashAndInvestments" order="10650.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="zfgn_OrganizationConsolidationAndPresentationOfFinancialStatementsDisclosureLineItems" xlink:to="us-gaap_CashCashEquivalentsAndShortTermInvestments" order="10740.00" priority="2" use="optional" />
  </definitionLink>
  <roleRef roleURI="http://www.zafgen.com/20181231/taxonomy/role/DisclosureSummaryOfSignificantAccountingPoliciesAdditionalInformationDetail" xlink:href="zfgn-20181231.xsd#Role_DisclosureSummaryOfSignificantAccountingPoliciesAdditionalInformationDetail" xlink:type="simple" />
  <definitionLink xlink:type="extended" xlink:role="http://www.zafgen.com/20181231/taxonomy/role/DisclosureSummaryOfSignificantAccountingPoliciesAdditionalInformationDetail">
    <loc xlink:href="zfgn-20181231.xsd#zfgn_LikelihoodPercentageMinimum" xlink:type="locator" xlink:label="zfgn_LikelihoodPercentageMinimum" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_ImpairmentOfIntangibleAssetsIndefinitelivedExcludingGoodwill" xlink:type="locator" xlink:label="us-gaap_ImpairmentOfIntangibleAssetsIndefinitelivedExcludingGoodwill" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_PropertyPlantAndEquipmentUsefulLife" xlink:type="locator" xlink:label="us-gaap_PropertyPlantAndEquipmentUsefulLife" />
    <loc xlink:href="http://xbrl.fasb.org/srt/2018/elts/srt-2018-01-31.xsd#srt_MaximumMember" xlink:type="locator" xlink:label="srt_MaximumMember" />
    <loc xlink:href="http://xbrl.fasb.org/srt/2018/elts/srt-2018-01-31.xsd#srt_MinimumMember" xlink:type="locator" xlink:label="srt_MinimumMember" />
    <loc xlink:href="http://xbrl.fasb.org/srt/2018/elts/srt-2018-01-31.xsd#srt_RangeMember" xlink:type="locator" xlink:label="srt_RangeMember" />
    <loc xlink:href="http://xbrl.fasb.org/srt/2018/elts/srt-2018-01-31.xsd#srt_RangeMember" xlink:type="locator" xlink:label="srt_RangeMember_2" />
    <loc xlink:href="http://xbrl.fasb.org/srt/2018/elts/srt-2018-01-31.xsd#srt_RangeAxis" xlink:type="locator" xlink:label="srt_RangeAxis" />
    <loc xlink:href="zfgn-20181231.xsd#zfgn_EquipmentFurnitureAndFixturesAndOfficeEquipmentMember" xlink:type="locator" xlink:label="zfgn_EquipmentFurnitureAndFixturesAndOfficeEquipmentMember" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_PropertyPlantAndEquipmentTypeDomain" xlink:type="locator" xlink:label="us-gaap_PropertyPlantAndEquipmentTypeDomain" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_PropertyPlantAndEquipmentTypeDomain" xlink:type="locator" xlink:label="us-gaap_PropertyPlantAndEquipmentTypeDomain_2" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_PropertyPlantAndEquipmentByTypeAxis" xlink:type="locator" xlink:label="us-gaap_PropertyPlantAndEquipmentByTypeAxis" />
    <loc xlink:href="zfgn-20181231.xsd#zfgn_SummaryOfSignificantAccountingPoliciesTable" xlink:type="locator" xlink:label="zfgn_SummaryOfSignificantAccountingPoliciesTable" />
    <loc xlink:href="zfgn-20181231.xsd#zfgn_SummaryOfSignificantAccountingPoliciesLineItems" xlink:type="locator" xlink:label="zfgn_SummaryOfSignificantAccountingPoliciesLineItems" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/all" xlink:from="zfgn_SummaryOfSignificantAccountingPoliciesLineItems" xlink:to="zfgn_SummaryOfSignificantAccountingPoliciesTable" order="10010.00" priority="2" use="optional" xbrldt:contextElement="segment" xbrldt:closed="true" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="zfgn_SummaryOfSignificantAccountingPoliciesTable" xlink:to="us-gaap_PropertyPlantAndEquipmentByTypeAxis" order="10040.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="us-gaap_PropertyPlantAndEquipmentByTypeAxis" xlink:to="us-gaap_PropertyPlantAndEquipmentTypeDomain_2" order="10050.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="us-gaap_PropertyPlantAndEquipmentByTypeAxis" xlink:to="us-gaap_PropertyPlantAndEquipmentTypeDomain" order="10070.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_PropertyPlantAndEquipmentTypeDomain" xlink:to="zfgn_EquipmentFurnitureAndFixturesAndOfficeEquipmentMember" order="10090.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="zfgn_SummaryOfSignificantAccountingPoliciesTable" xlink:to="srt_RangeAxis" order="10120.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="srt_RangeAxis" xlink:to="srt_RangeMember_2" order="10130.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="srt_RangeAxis" xlink:to="srt_RangeMember" order="10150.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="srt_RangeMember" xlink:to="srt_MinimumMember" order="10170.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="srt_RangeMember" xlink:to="srt_MaximumMember" order="10190.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="zfgn_SummaryOfSignificantAccountingPoliciesLineItems" xlink:to="us-gaap_PropertyPlantAndEquipmentUsefulLife" order="10220.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="zfgn_SummaryOfSignificantAccountingPoliciesLineItems" xlink:to="us-gaap_ImpairmentOfIntangibleAssetsIndefinitelivedExcludingGoodwill" order="10290.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="zfgn_SummaryOfSignificantAccountingPoliciesLineItems" xlink:to="zfgn_LikelihoodPercentageMinimum" order="10340.00" priority="2" use="optional" />
  </definitionLink>
  <roleRef roleURI="http://www.zafgen.com/20181231/taxonomy/role/DisclosureFairValueMeasurementsAndMarketableSecuritiesSummaryOfCashEquivalentsAndMarketableSecuritiesDetail" xlink:href="zfgn-20181231.xsd#Role_DisclosureFairValueMeasurementsAndMarketableSecuritiesSummaryOfCashEquivalentsAndMarketableSecuritiesDetail" xlink:type="simple" />
  <definitionLink xlink:type="extended" xlink:role="http://www.zafgen.com/20181231/taxonomy/role/DisclosureFairValueMeasurementsAndMarketableSecuritiesSummaryOfCashEquivalentsAndMarketableSecuritiesDetail">
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_AssetsFairValueDisclosure" xlink:type="locator" xlink:label="us-gaap_AssetsFairValueDisclosure" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_AvailableForSaleSecuritiesDebtSecuritiesCurrent" xlink:type="locator" xlink:label="us-gaap_AvailableForSaleSecuritiesDebtSecuritiesCurrent" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_CashAndCashEquivalentsFairValueDisclosure" xlink:type="locator" xlink:label="us-gaap_CashAndCashEquivalentsFairValueDisclosure" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_CertificatesOfDepositMember" xlink:type="locator" xlink:label="us-gaap_CertificatesOfDepositMember" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_FairValueInputsLevel3Member" xlink:type="locator" xlink:label="us-gaap_FairValueInputsLevel3Member" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_FairValueInputsLevel2Member" xlink:type="locator" xlink:label="us-gaap_FairValueInputsLevel2Member" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_FairValueInputsLevel1Member" xlink:type="locator" xlink:label="us-gaap_FairValueInputsLevel1Member" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_FairValueMeasurementsFairValueHierarchyDomain" xlink:type="locator" xlink:label="us-gaap_FairValueMeasurementsFairValueHierarchyDomain" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_FairValueMeasurementsFairValueHierarchyDomain" xlink:type="locator" xlink:label="us-gaap_FairValueMeasurementsFairValueHierarchyDomain_2" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_FairValueByFairValueHierarchyLevelAxis" xlink:type="locator" xlink:label="us-gaap_FairValueByFairValueHierarchyLevelAxis" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_USGovernmentCorporationsAndAgenciesSecuritiesMember" xlink:type="locator" xlink:label="us-gaap_USGovernmentCorporationsAndAgenciesSecuritiesMember" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_CorporateBondSecuritiesMember" xlink:type="locator" xlink:label="us-gaap_CorporateBondSecuritiesMember" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_CommercialPaperMember" xlink:type="locator" xlink:label="us-gaap_CommercialPaperMember" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_MoneyMarketFundsMember" xlink:type="locator" xlink:label="us-gaap_MoneyMarketFundsMember" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_InvestmentTypeCategorizationMember" xlink:type="locator" xlink:label="us-gaap_InvestmentTypeCategorizationMember" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_InvestmentTypeCategorizationMember" xlink:type="locator" xlink:label="us-gaap_InvestmentTypeCategorizationMember_2" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_InvestmentTypeAxis" xlink:type="locator" xlink:label="us-gaap_InvestmentTypeAxis" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_FairValueAssetsAndLiabilitiesMeasuredOnRecurringAndNonrecurringBasisTable" xlink:type="locator" xlink:label="us-gaap_FairValueAssetsAndLiabilitiesMeasuredOnRecurringAndNonrecurringBasisTable" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_FairValueAssetsAndLiabilitiesMeasuredOnRecurringAndNonrecurringBasisLineItems" xlink:type="locator" xlink:label="us-gaap_FairValueAssetsAndLiabilitiesMeasuredOnRecurringAndNonrecurringBasisLineItems" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/all" xlink:from="us-gaap_FairValueAssetsAndLiabilitiesMeasuredOnRecurringAndNonrecurringBasisLineItems" xlink:to="us-gaap_FairValueAssetsAndLiabilitiesMeasuredOnRecurringAndNonrecurringBasisTable" order="10030.00" priority="2" use="optional" xbrldt:contextElement="segment" xbrldt:closed="true" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="us-gaap_FairValueAssetsAndLiabilitiesMeasuredOnRecurringAndNonrecurringBasisTable" xlink:to="us-gaap_InvestmentTypeAxis" order="10060.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="us-gaap_InvestmentTypeAxis" xlink:to="us-gaap_InvestmentTypeCategorizationMember_2" order="10070.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="us-gaap_InvestmentTypeAxis" xlink:to="us-gaap_InvestmentTypeCategorizationMember" order="10090.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_InvestmentTypeCategorizationMember" xlink:to="us-gaap_MoneyMarketFundsMember" order="10110.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_InvestmentTypeCategorizationMember" xlink:to="us-gaap_CommercialPaperMember" order="10130.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_InvestmentTypeCategorizationMember" xlink:to="us-gaap_CorporateBondSecuritiesMember" order="10150.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_InvestmentTypeCategorizationMember" xlink:to="us-gaap_USGovernmentCorporationsAndAgenciesSecuritiesMember" order="10190.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="us-gaap_FairValueAssetsAndLiabilitiesMeasuredOnRecurringAndNonrecurringBasisTable" xlink:to="us-gaap_FairValueByFairValueHierarchyLevelAxis" order="10200.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="us-gaap_FairValueByFairValueHierarchyLevelAxis" xlink:to="us-gaap_FairValueMeasurementsFairValueHierarchyDomain_2" order="10210.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="us-gaap_FairValueByFairValueHierarchyLevelAxis" xlink:to="us-gaap_FairValueMeasurementsFairValueHierarchyDomain" order="10230.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_FairValueMeasurementsFairValueHierarchyDomain" xlink:to="us-gaap_FairValueInputsLevel1Member" order="10250.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_FairValueMeasurementsFairValueHierarchyDomain" xlink:to="us-gaap_FairValueInputsLevel2Member" order="10270.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_FairValueMeasurementsFairValueHierarchyDomain" xlink:to="us-gaap_FairValueInputsLevel3Member" order="10290.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_InvestmentTypeCategorizationMember" xlink:to="us-gaap_CertificatesOfDepositMember" order="10450.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_FairValueAssetsAndLiabilitiesMeasuredOnRecurringAndNonrecurringBasisLineItems" xlink:to="us-gaap_CashAndCashEquivalentsFairValueDisclosure" order="10580.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_FairValueAssetsAndLiabilitiesMeasuredOnRecurringAndNonrecurringBasisLineItems" xlink:to="us-gaap_AvailableForSaleSecuritiesDebtSecuritiesCurrent" order="10820.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_FairValueAssetsAndLiabilitiesMeasuredOnRecurringAndNonrecurringBasisLineItems" xlink:to="us-gaap_AssetsFairValueDisclosure" order="11140.00" priority="2" use="optional" />
  </definitionLink>
  <roleRef roleURI="http://www.zafgen.com/20181231/taxonomy/role/DisclosureFairValueMeasurementsAndMarketableSecuritiesSummaryOfMarketableSecuritiesDetail" xlink:href="zfgn-20181231.xsd#Role_DisclosureFairValueMeasurementsAndMarketableSecuritiesSummaryOfMarketableSecuritiesDetail" xlink:type="simple" />
  <definitionLink xlink:type="extended" xlink:role="http://www.zafgen.com/20181231/taxonomy/role/DisclosureFairValueMeasurementsAndMarketableSecuritiesSummaryOfMarketableSecuritiesDetail">
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_AvailableForSaleSecuritiesDebtSecuritiesCurrent" xlink:type="locator" xlink:label="us-gaap_AvailableForSaleSecuritiesDebtSecuritiesCurrent" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_AvailableForSaleDebtSecuritiesAccumulatedGrossUnrealizedLossBeforeTax" xlink:type="locator" xlink:label="us-gaap_AvailableForSaleDebtSecuritiesAccumulatedGrossUnrealizedLossBeforeTax" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_AvailableForSaleDebtSecuritiesAccumulatedGrossUnrealizedGainBeforeTax" xlink:type="locator" xlink:label="us-gaap_AvailableForSaleDebtSecuritiesAccumulatedGrossUnrealizedGainBeforeTax" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_AvailableForSaleDebtSecuritiesAmortizedCostBasis" xlink:type="locator" xlink:label="us-gaap_AvailableForSaleDebtSecuritiesAmortizedCostBasis" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_CertificatesOfDepositMember" xlink:type="locator" xlink:label="us-gaap_CertificatesOfDepositMember" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_USGovernmentCorporationsAndAgenciesSecuritiesMember" xlink:type="locator" xlink:label="us-gaap_USGovernmentCorporationsAndAgenciesSecuritiesMember" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_CommercialPaperMember" xlink:type="locator" xlink:label="us-gaap_CommercialPaperMember" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_CorporateBondSecuritiesMember" xlink:type="locator" xlink:label="us-gaap_CorporateBondSecuritiesMember" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_InvestmentTypeCategorizationMember" xlink:type="locator" xlink:label="us-gaap_InvestmentTypeCategorizationMember" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_InvestmentTypeAxis" xlink:type="locator" xlink:label="us-gaap_InvestmentTypeAxis" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_DebtSecuritiesAvailableForSaleTable" xlink:type="locator" xlink:label="us-gaap_DebtSecuritiesAvailableForSaleTable" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_ScheduleOfAvailableForSaleSecuritiesLineItems" xlink:type="locator" xlink:label="us-gaap_ScheduleOfAvailableForSaleSecuritiesLineItems" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/all" xlink:from="us-gaap_ScheduleOfAvailableForSaleSecuritiesLineItems" xlink:to="us-gaap_DebtSecuritiesAvailableForSaleTable" order="10040.00" priority="2" use="optional" xbrldt:contextElement="segment" xbrldt:closed="true" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="us-gaap_DebtSecuritiesAvailableForSaleTable" xlink:to="us-gaap_InvestmentTypeAxis" order="10070.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="us-gaap_InvestmentTypeAxis" xlink:to="us-gaap_InvestmentTypeCategorizationMember" order="10100.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_InvestmentTypeCategorizationMember" xlink:to="us-gaap_CorporateBondSecuritiesMember" order="10120.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_InvestmentTypeCategorizationMember" xlink:to="us-gaap_CommercialPaperMember" order="10140.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_InvestmentTypeCategorizationMember" xlink:to="us-gaap_USGovernmentCorporationsAndAgenciesSecuritiesMember" order="10160.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_InvestmentTypeCategorizationMember" xlink:to="us-gaap_CertificatesOfDepositMember" order="10260.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ScheduleOfAvailableForSaleSecuritiesLineItems" xlink:to="us-gaap_AvailableForSaleDebtSecuritiesAmortizedCostBasis" order="10290.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ScheduleOfAvailableForSaleSecuritiesLineItems" xlink:to="us-gaap_AvailableForSaleDebtSecuritiesAccumulatedGrossUnrealizedGainBeforeTax" order="10490.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ScheduleOfAvailableForSaleSecuritiesLineItems" xlink:to="us-gaap_AvailableForSaleDebtSecuritiesAccumulatedGrossUnrealizedLossBeforeTax" order="10690.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ScheduleOfAvailableForSaleSecuritiesLineItems" xlink:to="us-gaap_AvailableForSaleSecuritiesDebtSecuritiesCurrent" order="10890.00" priority="2" use="optional" />
  </definitionLink>
  <roleRef roleURI="http://www.zafgen.com/20181231/taxonomy/role/DisclosurePropertyAndEquipmentNetScheduleOfPropertyPlantAndEquipmentNetDetail" xlink:href="zfgn-20181231.xsd#Role_DisclosurePropertyAndEquipmentNetScheduleOfPropertyPlantAndEquipmentNetDetail" xlink:type="simple" />
  <definitionLink xlink:type="extended" xlink:role="http://www.zafgen.com/20181231/taxonomy/role/DisclosurePropertyAndEquipmentNetScheduleOfPropertyPlantAndEquipmentNetDetail">
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_PropertyPlantAndEquipmentNet" xlink:type="locator" xlink:label="us-gaap_PropertyPlantAndEquipmentNet" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_AccumulatedDepreciationDepletionAndAmortizationPropertyPlantAndEquipment" xlink:type="locator" xlink:label="us-gaap_AccumulatedDepreciationDepletionAndAmortizationPropertyPlantAndEquipment" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_PropertyPlantAndEquipmentGross" xlink:type="locator" xlink:label="us-gaap_PropertyPlantAndEquipmentGross" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_PropertyPlantAndEquipmentUsefulLife" xlink:type="locator" xlink:label="us-gaap_PropertyPlantAndEquipmentUsefulLife" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_LeaseholdImprovementsMember" xlink:type="locator" xlink:label="us-gaap_LeaseholdImprovementsMember" />
    <loc xlink:href="http://xbrl.fasb.org/srt/2018/elts/srt-2018-01-31.xsd#srt_MaximumMember" xlink:type="locator" xlink:label="srt_MaximumMember" />
    <loc xlink:href="http://xbrl.fasb.org/srt/2018/elts/srt-2018-01-31.xsd#srt_MinimumMember" xlink:type="locator" xlink:label="srt_MinimumMember" />
    <loc xlink:href="http://xbrl.fasb.org/srt/2018/elts/srt-2018-01-31.xsd#srt_RangeMember" xlink:type="locator" xlink:label="srt_RangeMember" />
    <loc xlink:href="http://xbrl.fasb.org/srt/2018/elts/srt-2018-01-31.xsd#srt_RangeAxis" xlink:type="locator" xlink:label="srt_RangeAxis" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_EquipmentMember" xlink:type="locator" xlink:label="us-gaap_EquipmentMember" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_FurnitureAndFixturesMember" xlink:type="locator" xlink:label="us-gaap_FurnitureAndFixturesMember" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_OfficeEquipmentMember" xlink:type="locator" xlink:label="us-gaap_OfficeEquipmentMember" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_PropertyPlantAndEquipmentTypeDomain" xlink:type="locator" xlink:label="us-gaap_PropertyPlantAndEquipmentTypeDomain" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_PropertyPlantAndEquipmentByTypeAxis" xlink:type="locator" xlink:label="us-gaap_PropertyPlantAndEquipmentByTypeAxis" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_ScheduleOfPropertyPlantAndEquipmentTable" xlink:type="locator" xlink:label="us-gaap_ScheduleOfPropertyPlantAndEquipmentTable" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_PropertyPlantAndEquipmentLineItems" xlink:type="locator" xlink:label="us-gaap_PropertyPlantAndEquipmentLineItems" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/all" xlink:from="us-gaap_PropertyPlantAndEquipmentLineItems" xlink:to="us-gaap_ScheduleOfPropertyPlantAndEquipmentTable" order="10010.00" priority="2" use="optional" xbrldt:contextElement="segment" xbrldt:closed="true" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="us-gaap_ScheduleOfPropertyPlantAndEquipmentTable" xlink:to="us-gaap_PropertyPlantAndEquipmentByTypeAxis" order="10040.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="us-gaap_PropertyPlantAndEquipmentByTypeAxis" xlink:to="us-gaap_PropertyPlantAndEquipmentTypeDomain" order="10070.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_PropertyPlantAndEquipmentTypeDomain" xlink:to="us-gaap_OfficeEquipmentMember" order="10090.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_PropertyPlantAndEquipmentTypeDomain" xlink:to="us-gaap_FurnitureAndFixturesMember" order="10110.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_PropertyPlantAndEquipmentTypeDomain" xlink:to="us-gaap_EquipmentMember" order="10130.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="us-gaap_ScheduleOfPropertyPlantAndEquipmentTable" xlink:to="srt_RangeAxis" order="10140.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="srt_RangeAxis" xlink:to="srt_RangeMember" order="10170.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="srt_RangeMember" xlink:to="srt_MinimumMember" order="10190.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="srt_RangeMember" xlink:to="srt_MaximumMember" order="10210.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_PropertyPlantAndEquipmentTypeDomain" xlink:to="us-gaap_LeaseholdImprovementsMember" order="10330.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_PropertyPlantAndEquipmentLineItems" xlink:to="us-gaap_PropertyPlantAndEquipmentUsefulLife" order="10360.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_PropertyPlantAndEquipmentLineItems" xlink:to="us-gaap_PropertyPlantAndEquipmentGross" order="10590.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_PropertyPlantAndEquipmentLineItems" xlink:to="us-gaap_AccumulatedDepreciationDepletionAndAmortizationPropertyPlantAndEquipment" order="10790.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_PropertyPlantAndEquipmentLineItems" xlink:to="us-gaap_PropertyPlantAndEquipmentNet" order="10830.00" priority="2" use="optional" />
  </definitionLink>
  <roleRef roleURI="http://www.zafgen.com/20181231/taxonomy/role/DisclosureNotesPayableAdditionalInformationDetail" xlink:href="zfgn-20181231.xsd#Role_DisclosureNotesPayableAdditionalInformationDetail" xlink:type="simple" />
  <definitionLink xlink:type="extended" xlink:role="http://www.zafgen.com/20181231/taxonomy/role/DisclosureNotesPayableAdditionalInformationDetail">
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_LineOfCreditFacilityPeriodicPaymentInterest" xlink:type="locator" xlink:label="us-gaap_LineOfCreditFacilityPeriodicPaymentInterest" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_DebtInstrumentPeriodicPaymentInterest" xlink:type="locator" xlink:label="us-gaap_DebtInstrumentPeriodicPaymentInterest" />
    <loc xlink:href="zfgn-20181231.xsd#zfgn_LineOfCreditFacilityDebtDefaultMinimumAmount" xlink:type="locator" xlink:label="zfgn_LineOfCreditFacilityDebtDefaultMinimumAmount" />
    <loc xlink:href="zfgn-20181231.xsd#zfgn_DebtInstrumentRestrictiveCovenantsInvestmentInSubsidiaries" xlink:type="locator" xlink:label="zfgn_DebtInstrumentRestrictiveCovenantsInvestmentInSubsidiaries" />
    <loc xlink:href="zfgn-20181231.xsd#zfgn_PercentageOfPrincipalBalanceToBeSecuredInRestrictedCashAccount" xlink:type="locator" xlink:label="zfgn_PercentageOfPrincipalBalanceToBeSecuredInRestrictedCashAccount" />
    <loc xlink:href="zfgn-20181231.xsd#zfgn_CashCashEquivalentsAndShortTermInvestmentsPercentage" xlink:type="locator" xlink:label="zfgn_CashCashEquivalentsAndShortTermInvestmentsPercentage" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_CashCashEquivalentsAndShortTermInvestments" xlink:type="locator" xlink:label="us-gaap_CashCashEquivalentsAndShortTermInvestments" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_DebtInstrumentCovenantDescription" xlink:type="locator" xlink:label="us-gaap_DebtInstrumentCovenantDescription" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_RestrictedCashAndInvestments" xlink:type="locator" xlink:label="us-gaap_RestrictedCashAndInvestments" />
    <loc xlink:href="zfgn-20181231.xsd#zfgn_RestrictedCashAndInvestmentsAsPercentageOfOutstandingPrincipalAmount" xlink:type="locator" xlink:label="zfgn_RestrictedCashAndInvestmentsAsPercentageOfOutstandingPrincipalAmount" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_DebtInstrumentInterestRateDuringPeriod" xlink:type="locator" xlink:label="us-gaap_DebtInstrumentInterestRateDuringPeriod" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_DebtInstrumentIncreaseAccruedInterest" xlink:type="locator" xlink:label="us-gaap_DebtInstrumentIncreaseAccruedInterest" />
    <loc xlink:href="zfgn-20181231.xsd#zfgn_DebtInstrumentFeePercentage" xlink:type="locator" xlink:label="zfgn_DebtInstrumentFeePercentage" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_DebtInstrumentInterestRateEffectivePercentage" xlink:type="locator" xlink:label="us-gaap_DebtInstrumentInterestRateEffectivePercentage" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_DebtInstrumentBasisSpreadOnVariableRate1" xlink:type="locator" xlink:label="us-gaap_DebtInstrumentBasisSpreadOnVariableRate1" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_DebtInstrumentDescriptionOfVariableRateBasis" xlink:type="locator" xlink:label="us-gaap_DebtInstrumentDescriptionOfVariableRateBasis" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_DebtInstrumentMaturityDate" xlink:type="locator" xlink:label="us-gaap_DebtInstrumentMaturityDate" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_DebtInstrumentDescription" xlink:type="locator" xlink:label="us-gaap_DebtInstrumentDescription" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_ProceedsFromNotesPayable" xlink:type="locator" xlink:label="us-gaap_ProceedsFromNotesPayable" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_DebtInstrumentFaceAmount" xlink:type="locator" xlink:label="us-gaap_DebtInstrumentFaceAmount" />
    <loc xlink:href="zfgn-20181231.xsd#zfgn_TwoThousandAndFourteenCreditFacilityMember" xlink:type="locator" xlink:label="zfgn_TwoThousandAndFourteenCreditFacilityMember" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_CreditFacilityDomain" xlink:type="locator" xlink:label="us-gaap_CreditFacilityDomain" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_CreditFacilityDomain" xlink:type="locator" xlink:label="us-gaap_CreditFacilityDomain_2" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_CreditFacilityAxis" xlink:type="locator" xlink:label="us-gaap_CreditFacilityAxis" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_SecuredDebtMember" xlink:type="locator" xlink:label="us-gaap_SecuredDebtMember" />
    <loc xlink:href="http://xbrl.fasb.org/srt/2018/elts/srt-2018-01-31.xsd#srt_MaximumMember" xlink:type="locator" xlink:label="srt_MaximumMember" />
    <loc xlink:href="http://xbrl.fasb.org/srt/2018/elts/srt-2018-01-31.xsd#srt_MinimumMember" xlink:type="locator" xlink:label="srt_MinimumMember" />
    <loc xlink:href="http://xbrl.fasb.org/srt/2018/elts/srt-2018-01-31.xsd#srt_RangeMember" xlink:type="locator" xlink:label="srt_RangeMember" />
    <loc xlink:href="http://xbrl.fasb.org/srt/2018/elts/srt-2018-01-31.xsd#srt_RangeAxis" xlink:type="locator" xlink:label="srt_RangeAxis" />
    <loc xlink:href="zfgn-20181231.xsd#zfgn_TermLoanMember" xlink:type="locator" xlink:label="zfgn_TermLoanMember" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_LongtermDebtTypeDomain" xlink:type="locator" xlink:label="us-gaap_LongtermDebtTypeDomain" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_LongtermDebtTypeAxis" xlink:type="locator" xlink:label="us-gaap_LongtermDebtTypeAxis" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_DebtInstrumentTable" xlink:type="locator" xlink:label="us-gaap_DebtInstrumentTable" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_DebtInstrumentLineItems" xlink:type="locator" xlink:label="us-gaap_DebtInstrumentLineItems" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/all" xlink:from="us-gaap_DebtInstrumentLineItems" xlink:to="us-gaap_DebtInstrumentTable" order="10010.00" priority="2" use="optional" xbrldt:contextElement="segment" xbrldt:closed="true" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="us-gaap_DebtInstrumentTable" xlink:to="us-gaap_LongtermDebtTypeAxis" order="10040.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="us-gaap_LongtermDebtTypeAxis" xlink:to="us-gaap_LongtermDebtTypeDomain" order="10070.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_LongtermDebtTypeDomain" xlink:to="zfgn_TermLoanMember" order="10090.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="us-gaap_DebtInstrumentTable" xlink:to="srt_RangeAxis" order="10420.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="srt_RangeAxis" xlink:to="srt_RangeMember" order="10450.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="srt_RangeMember" xlink:to="srt_MinimumMember" order="10470.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="srt_RangeMember" xlink:to="srt_MaximumMember" order="10490.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_LongtermDebtTypeDomain" xlink:to="us-gaap_SecuredDebtMember" order="10870.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="us-gaap_DebtInstrumentTable" xlink:to="us-gaap_CreditFacilityAxis" order="10960.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="us-gaap_CreditFacilityAxis" xlink:to="us-gaap_CreditFacilityDomain_2" order="10970.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="us-gaap_CreditFacilityAxis" xlink:to="us-gaap_CreditFacilityDomain" order="10990.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_CreditFacilityDomain" xlink:to="zfgn_TwoThousandAndFourteenCreditFacilityMember" order="11010.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_DebtInstrumentLineItems" xlink:to="us-gaap_DebtInstrumentFaceAmount" order="11040.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_DebtInstrumentLineItems" xlink:to="us-gaap_ProceedsFromNotesPayable" order="11060.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_DebtInstrumentLineItems" xlink:to="us-gaap_DebtInstrumentDescription" order="11110.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_DebtInstrumentLineItems" xlink:to="us-gaap_DebtInstrumentMaturityDate" order="11130.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_DebtInstrumentLineItems" xlink:to="us-gaap_DebtInstrumentDescriptionOfVariableRateBasis" order="11150.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_DebtInstrumentLineItems" xlink:to="us-gaap_DebtInstrumentBasisSpreadOnVariableRate1" order="11170.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_DebtInstrumentLineItems" xlink:to="us-gaap_DebtInstrumentInterestRateEffectivePercentage" order="11190.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_DebtInstrumentLineItems" xlink:to="zfgn_DebtInstrumentFeePercentage" order="11210.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_DebtInstrumentLineItems" xlink:to="us-gaap_DebtInstrumentIncreaseAccruedInterest" order="11230.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_DebtInstrumentLineItems" xlink:to="us-gaap_DebtInstrumentInterestRateDuringPeriod" order="11280.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_DebtInstrumentLineItems" xlink:to="zfgn_RestrictedCashAndInvestmentsAsPercentageOfOutstandingPrincipalAmount" order="11330.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_DebtInstrumentLineItems" xlink:to="us-gaap_RestrictedCashAndInvestments" order="11370.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_DebtInstrumentLineItems" xlink:to="us-gaap_DebtInstrumentCovenantDescription" order="11440.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_DebtInstrumentLineItems" xlink:to="us-gaap_CashCashEquivalentsAndShortTermInvestments" order="11460.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_DebtInstrumentLineItems" xlink:to="zfgn_CashCashEquivalentsAndShortTermInvestmentsPercentage" order="11480.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_DebtInstrumentLineItems" xlink:to="zfgn_PercentageOfPrincipalBalanceToBeSecuredInRestrictedCashAccount" order="11500.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_DebtInstrumentLineItems" xlink:to="zfgn_DebtInstrumentRestrictiveCovenantsInvestmentInSubsidiaries" order="11550.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_DebtInstrumentLineItems" xlink:to="zfgn_LineOfCreditFacilityDebtDefaultMinimumAmount" order="11600.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_DebtInstrumentLineItems" xlink:to="us-gaap_DebtInstrumentPeriodicPaymentInterest" order="11650.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_DebtInstrumentLineItems" xlink:to="us-gaap_LineOfCreditFacilityPeriodicPaymentInterest" order="11730.00" priority="2" use="optional" />
  </definitionLink>
  <roleRef roleURI="http://www.zafgen.com/20181231/taxonomy/role/DisclosureStockholdersEquityAdditionalInformationDetail" xlink:href="zfgn-20181231.xsd#Role_DisclosureStockholdersEquityAdditionalInformationDetail" xlink:type="simple" />
  <definitionLink xlink:type="extended" xlink:role="http://www.zafgen.com/20181231/taxonomy/role/DisclosureStockholdersEquityAdditionalInformationDetail">
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_CommonStockParOrStatedValuePerShare" xlink:type="locator" xlink:label="us-gaap_CommonStockParOrStatedValuePerShare" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_CommonStockSharesAuthorized" xlink:type="locator" xlink:label="us-gaap_CommonStockSharesAuthorized" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_PreferredStockParOrStatedValuePerShare" xlink:type="locator" xlink:label="us-gaap_PreferredStockParOrStatedValuePerShare" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_PreferredStockSharesAuthorized" xlink:type="locator" xlink:label="us-gaap_PreferredStockSharesAuthorized" />
    <loc xlink:href="zfgn-20181231.xsd#zfgn_SalesAgreementDescription" xlink:type="locator" xlink:label="zfgn_SalesAgreementDescription" />
    <loc xlink:href="zfgn-20181231.xsd#zfgn_PercentageOfCompensationForServicesEqualToGrossProceeds" xlink:type="locator" xlink:label="zfgn_PercentageOfCompensationForServicesEqualToGrossProceeds" />
    <loc xlink:href="zfgn-20181231.xsd#zfgn_AggregateGrossSalesProceedsUnderSalesAgreement" xlink:type="locator" xlink:label="zfgn_AggregateGrossSalesProceedsUnderSalesAgreement" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_ProceedsFromIssuanceOfCommonStock" xlink:type="locator" xlink:label="us-gaap_ProceedsFromIssuanceOfCommonStock" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_SharesIssuedPricePerShare" xlink:type="locator" xlink:label="us-gaap_SharesIssuedPricePerShare" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_StockIssuedDuringPeriodSharesNewIssues" xlink:type="locator" xlink:label="us-gaap_StockIssuedDuringPeriodSharesNewIssues" />
    <loc xlink:href="http://xbrl.fasb.org/srt/2018/elts/srt-2018-01-31.xsd#srt_MinimumMember" xlink:type="locator" xlink:label="srt_MinimumMember" />
    <loc xlink:href="http://xbrl.fasb.org/srt/2018/elts/srt-2018-01-31.xsd#srt_MaximumMember" xlink:type="locator" xlink:label="srt_MaximumMember" />
    <loc xlink:href="http://xbrl.fasb.org/srt/2018/elts/srt-2018-01-31.xsd#srt_RangeMember" xlink:type="locator" xlink:label="srt_RangeMember" />
    <loc xlink:href="http://xbrl.fasb.org/srt/2018/elts/srt-2018-01-31.xsd#srt_RangeAxis" xlink:type="locator" xlink:label="srt_RangeAxis" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_CommonStockMember" xlink:type="locator" xlink:label="us-gaap_CommonStockMember" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_EquityComponentDomain" xlink:type="locator" xlink:label="us-gaap_EquityComponentDomain" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_StatementEquityComponentsAxis" xlink:type="locator" xlink:label="us-gaap_StatementEquityComponentsAxis" />
    <loc xlink:href="zfgn-20181231.xsd#zfgn_AtTheMarketEquityOfferingProgramMember" xlink:type="locator" xlink:label="zfgn_AtTheMarketEquityOfferingProgramMember" />
    <loc xlink:href="zfgn-20181231.xsd#zfgn_CowenAndCompanyLimitedLiabilityCompanyMember" xlink:type="locator" xlink:label="zfgn_CowenAndCompanyLimitedLiabilityCompanyMember" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_RelatedPartyDomain" xlink:type="locator" xlink:label="us-gaap_RelatedPartyDomain" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_RelatedPartyDomain" xlink:type="locator" xlink:label="us-gaap_RelatedPartyDomain_2" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_RelatedPartyTransactionsByRelatedPartyAxis" xlink:type="locator" xlink:label="us-gaap_RelatedPartyTransactionsByRelatedPartyAxis" />
    <loc xlink:href="zfgn-20181231.xsd#zfgn_PublicOfferingMember" xlink:type="locator" xlink:label="zfgn_PublicOfferingMember" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_SaleOfStockNameOfTransactionDomain" xlink:type="locator" xlink:label="us-gaap_SaleOfStockNameOfTransactionDomain" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_SubsidiarySaleOfStockAxis" xlink:type="locator" xlink:label="us-gaap_SubsidiarySaleOfStockAxis" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_StatementTable" xlink:type="locator" xlink:label="us-gaap_StatementTable" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_StatementLineItems" xlink:type="locator" xlink:label="us-gaap_StatementLineItems" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/all" xlink:from="us-gaap_StatementLineItems" xlink:to="us-gaap_StatementTable" order="10010.00" priority="2" use="optional" xbrldt:contextElement="segment" xbrldt:closed="true" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="us-gaap_StatementTable" xlink:to="us-gaap_SubsidiarySaleOfStockAxis" order="10040.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="us-gaap_SubsidiarySaleOfStockAxis" xlink:to="us-gaap_SaleOfStockNameOfTransactionDomain" order="10070.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_SaleOfStockNameOfTransactionDomain" xlink:to="zfgn_PublicOfferingMember" order="10090.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="us-gaap_StatementTable" xlink:to="us-gaap_RelatedPartyTransactionsByRelatedPartyAxis" order="10140.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="us-gaap_RelatedPartyTransactionsByRelatedPartyAxis" xlink:to="us-gaap_RelatedPartyDomain_2" order="10150.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="us-gaap_RelatedPartyTransactionsByRelatedPartyAxis" xlink:to="us-gaap_RelatedPartyDomain" order="10170.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_RelatedPartyDomain" xlink:to="zfgn_CowenAndCompanyLimitedLiabilityCompanyMember" order="10190.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_SaleOfStockNameOfTransactionDomain" xlink:to="zfgn_AtTheMarketEquityOfferingProgramMember" order="10250.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="us-gaap_StatementTable" xlink:to="us-gaap_StatementEquityComponentsAxis" order="10320.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="us-gaap_StatementEquityComponentsAxis" xlink:to="us-gaap_EquityComponentDomain" order="10350.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_EquityComponentDomain" xlink:to="us-gaap_CommonStockMember" order="10370.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="us-gaap_StatementTable" xlink:to="srt_RangeAxis" order="10420.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="srt_RangeAxis" xlink:to="srt_RangeMember" order="10450.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="srt_RangeMember" xlink:to="srt_MaximumMember" order="10470.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="srt_RangeMember" xlink:to="srt_MinimumMember" order="10490.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_StatementLineItems" xlink:to="us-gaap_StockIssuedDuringPeriodSharesNewIssues" order="10520.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_StatementLineItems" xlink:to="us-gaap_SharesIssuedPricePerShare" order="10560.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_StatementLineItems" xlink:to="us-gaap_ProceedsFromIssuanceOfCommonStock" order="10600.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_StatementLineItems" xlink:to="zfgn_AggregateGrossSalesProceedsUnderSalesAgreement" order="10670.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_StatementLineItems" xlink:to="zfgn_PercentageOfCompensationForServicesEqualToGrossProceeds" order="10710.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_StatementLineItems" xlink:to="zfgn_SalesAgreementDescription" order="10750.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_StatementLineItems" xlink:to="us-gaap_PreferredStockSharesAuthorized" order="10860.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_StatementLineItems" xlink:to="us-gaap_PreferredStockParOrStatedValuePerShare" order="10900.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_StatementLineItems" xlink:to="us-gaap_CommonStockSharesAuthorized" order="10970.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_StatementLineItems" xlink:to="us-gaap_CommonStockParOrStatedValuePerShare" order="11010.00" priority="2" use="optional" />
  </definitionLink>
  <roleRef roleURI="http://www.zafgen.com/20181231/taxonomy/role/DisclosureStockBasedAwardsAdditionalInformationDetail" xlink:href="zfgn-20181231.xsd#Role_DisclosureStockBasedAwardsAdditionalInformationDetail" xlink:type="simple" />
  <definitionLink xlink:type="extended" xlink:role="http://www.zafgen.com/20181231/taxonomy/role/DisclosureStockBasedAwardsAdditionalInformationDetail">
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_EmployeeServiceShareBasedCompensationNonvestedAwardsTotalCompensationCostNotYetRecognizedPeriodForRecognition1" xlink:type="locator" xlink:label="us-gaap_EmployeeServiceShareBasedCompensationNonvestedAwardsTotalCompensationCostNotYetRecognizedPeriodForRecognition1" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_EmployeeServiceShareBasedCompensationNonvestedAwardsTotalCompensationCostNotYetRecognized" xlink:type="locator" xlink:label="us-gaap_EmployeeServiceShareBasedCompensationNonvestedAwardsTotalCompensationCostNotYetRecognized" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_StockOptionPlanExpense" xlink:type="locator" xlink:label="us-gaap_StockOptionPlanExpense" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_StockIssuedDuringPeriodSharesShareBasedCompensation" xlink:type="locator" xlink:label="us-gaap_StockIssuedDuringPeriodSharesShareBasedCompensation" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardDiscountFromMarketPriceOfferingDate" xlink:type="locator" xlink:label="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardDiscountFromMarketPriceOfferingDate" />
    <loc xlink:href="zfgn-20181231.xsd#zfgn_SecondOfferingPeriodEndDate" xlink:type="locator" xlink:label="zfgn_SecondOfferingPeriodEndDate" />
    <loc xlink:href="zfgn-20181231.xsd#zfgn_SecondOfferingPeriodStartDate" xlink:type="locator" xlink:label="zfgn_SecondOfferingPeriodStartDate" />
    <loc xlink:href="zfgn-20181231.xsd#zfgn_FirstOfferingPeriodEndDate" xlink:type="locator" xlink:label="zfgn_FirstOfferingPeriodEndDate" />
    <loc xlink:href="zfgn-20181231.xsd#zfgn_FirstOfferingPeriodStartDate" xlink:type="locator" xlink:label="zfgn_FirstOfferingPeriodStartDate" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardEquityInstrumentsOtherThanOptionsNonvestedNumber" xlink:type="locator" xlink:label="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardEquityInstrumentsOtherThanOptionsNonvestedNumber" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardEquityInstrumentsOtherThanOptionsVestedInPeriodWeightedAverageGrantDateFairValue" xlink:type="locator" xlink:label="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardEquityInstrumentsOtherThanOptionsVestedInPeriodWeightedAverageGrantDateFairValue" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardEquityInstrumentsOtherThanOptionsGrantsInPeriod" xlink:type="locator" xlink:label="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardEquityInstrumentsOtherThanOptionsGrantsInPeriod" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardEquityInstrumentsOtherThanOptionsAggregateIntrinsicValueVested" xlink:type="locator" xlink:label="us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardEquityInstrumentsOtherThanOptionsAggregateIntrinsicValueVested" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardOptionsOutstandingWeightedAverageRemainingContractualTerm2" xlink:type="locator" xlink:label="us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardOptionsOutstandingWeightedAverageRemainingContractualTerm2" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsOutstandingIntrinsicValue" xlink:type="locator" xlink:label="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsOutstandingIntrinsicValue" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardOptionsVestedWeightedAverageGrantDateFairValue" xlink:type="locator" xlink:label="us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardOptionsVestedWeightedAverageGrantDateFairValue" />
    <loc xlink:href="zfgn-20181231.xsd#zfgn_ShareBasedCompensationArrangementByShareBasedPaymentAwardAggregateGrantDateFairValue" xlink:type="locator" xlink:label="zfgn_ShareBasedCompensationArrangementByShareBasedPaymentAwardAggregateGrantDateFairValue" />
    <loc xlink:href="zfgn-20181231.xsd#zfgn_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsGrantTargetSharesPercentage" xlink:type="locator" xlink:label="zfgn_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsGrantTargetSharesPercentage" />
    <loc xlink:href="zfgn-20181231.xsd#zfgn_ShareBasedCompensationArrangementByShareBasedPaymentAwardDateOfGrantedShareForfeited" xlink:type="locator" xlink:label="zfgn_ShareBasedCompensationArrangementByShareBasedPaymentAwardDateOfGrantedShareForfeited" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsForfeituresInPeriod" xlink:type="locator" xlink:label="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsForfeituresInPeriod" />
    <loc xlink:href="zfgn-20181231.xsd#zfgn_ConsecutivePeriodOfMinimumCommonStockPriceDuringEarningPeriodDescription" xlink:type="locator" xlink:label="zfgn_ConsecutivePeriodOfMinimumCommonStockPriceDuringEarningPeriodDescription" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardOptionsNonvestedNumberOfShares" xlink:type="locator" xlink:label="us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardOptionsNonvestedNumberOfShares" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsGrantsInPeriodWeightedAverageGrantDateFairValue" xlink:type="locator" xlink:label="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsGrantsInPeriodWeightedAverageGrantDateFairValue" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_ProceedsFromStockOptionsExercised" xlink:type="locator" xlink:label="us-gaap_ProceedsFromStockOptionsExercised" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsExercisesInPeriodTotalIntrinsicValue" xlink:type="locator" xlink:label="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsExercisesInPeriodTotalIntrinsicValue" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardDescription" xlink:type="locator" xlink:label="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardDescription" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardAwardVestingRightsPercentage" xlink:type="locator" xlink:label="us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardAwardVestingRightsPercentage" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardExpirationPeriod" xlink:type="locator" xlink:label="us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardExpirationPeriod" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardAwardVestingPeriod1" xlink:type="locator" xlink:label="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardAwardVestingPeriod1" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsGrantsInPeriodGross" xlink:type="locator" xlink:label="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsGrantsInPeriodGross" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsOtherIncreasesDecreasesInPeriod" xlink:type="locator" xlink:label="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsOtherIncreasesDecreasesInPeriod" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfSharesAvailableForGrant" xlink:type="locator" xlink:label="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfSharesAvailableForGrant" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardPercentageOfOutstandingStockMaximum" xlink:type="locator" xlink:label="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardPercentageOfOutstandingStockMaximum" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_CommonStockCapitalSharesReservedForFutureIssuance" xlink:type="locator" xlink:label="us-gaap_CommonStockCapitalSharesReservedForFutureIssuance" />
    <loc xlink:href="zfgn-20181231.xsd#zfgn_MarketBasedStockOptionsMember" xlink:type="locator" xlink:label="zfgn_MarketBasedStockOptionsMember" />
    <loc xlink:href="zfgn-20181231.xsd#zfgn_TimeBasedOptionsMember" xlink:type="locator" xlink:label="zfgn_TimeBasedOptionsMember" />
    <loc xlink:href="zfgn-20181231.xsd#zfgn_TwoThousandAndFourteenEmployeeStockPurchasePlanMember" xlink:type="locator" xlink:label="zfgn_TwoThousandAndFourteenEmployeeStockPurchasePlanMember" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_RestrictedStockUnitsRSUMember" xlink:type="locator" xlink:label="us-gaap_RestrictedStockUnitsRSUMember" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_EmployeeStockOptionMember" xlink:type="locator" xlink:label="us-gaap_EmployeeStockOptionMember" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_OptionIndexedToIssuersEquityTypeDomain" xlink:type="locator" xlink:label="us-gaap_OptionIndexedToIssuersEquityTypeDomain" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_OptionIndexedToIssuersEquityTypeDomain" xlink:type="locator" xlink:label="us-gaap_OptionIndexedToIssuersEquityTypeDomain_2" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_OptionIndexedToIssuersEquityTypeAxis" xlink:type="locator" xlink:label="us-gaap_OptionIndexedToIssuersEquityTypeAxis" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_ChiefExecutiveOfficerMember" xlink:type="locator" xlink:label="us-gaap_ChiefExecutiveOfficerMember" />
    <loc xlink:href="zfgn-20181231.xsd#zfgn_MarketBasedVestingConditionsMember" xlink:type="locator" xlink:label="zfgn_MarketBasedVestingConditionsMember" />
    <loc xlink:href="zfgn-20181231.xsd#zfgn_NonemployeeMember" xlink:type="locator" xlink:label="zfgn_NonemployeeMember" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_TitleOfIndividualWithRelationshipToEntityDomain" xlink:type="locator" xlink:label="us-gaap_TitleOfIndividualWithRelationshipToEntityDomain" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_TitleOfIndividualWithRelationshipToEntityDomain" xlink:type="locator" xlink:label="us-gaap_TitleOfIndividualWithRelationshipToEntityDomain_2" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_TitleOfIndividualAxis" xlink:type="locator" xlink:label="us-gaap_TitleOfIndividualAxis" />
    <loc xlink:href="http://xbrl.fasb.org/srt/2018/elts/srt-2018-01-31.xsd#srt_MaximumMember" xlink:type="locator" xlink:label="srt_MaximumMember" />
    <loc xlink:href="http://xbrl.fasb.org/srt/2018/elts/srt-2018-01-31.xsd#srt_MinimumMember" xlink:type="locator" xlink:label="srt_MinimumMember" />
    <loc xlink:href="http://xbrl.fasb.org/srt/2018/elts/srt-2018-01-31.xsd#srt_RangeMember" xlink:type="locator" xlink:label="srt_RangeMember" />
    <loc xlink:href="http://xbrl.fasb.org/srt/2018/elts/srt-2018-01-31.xsd#srt_RangeAxis" xlink:type="locator" xlink:label="srt_RangeAxis" />
    <loc xlink:href="zfgn-20181231.xsd#zfgn_TimeBasedVestingMember" xlink:type="locator" xlink:label="zfgn_TimeBasedVestingMember" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_ShareBasedCompensationArrangementsByShareBasedPaymentAwardAwardTypeAndPlanNameDomain" xlink:type="locator" xlink:label="us-gaap_ShareBasedCompensationArrangementsByShareBasedPaymentAwardAwardTypeAndPlanNameDomain" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_AwardTypeAxis" xlink:type="locator" xlink:label="us-gaap_AwardTypeAxis" />
    <loc xlink:href="zfgn-20181231.xsd#zfgn_GrantsOutsideOfTwoThousandFourteenPlanMember" xlink:type="locator" xlink:label="zfgn_GrantsOutsideOfTwoThousandFourteenPlanMember" />
    <loc xlink:href="zfgn-20181231.xsd#zfgn_TwoThousandFourteenStockOptionMember" xlink:type="locator" xlink:label="zfgn_TwoThousandFourteenStockOptionMember" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_PlanNameDomain" xlink:type="locator" xlink:label="us-gaap_PlanNameDomain" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_PlanNameDomain" xlink:type="locator" xlink:label="us-gaap_PlanNameDomain_2" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_PlanNameAxis" xlink:type="locator" xlink:label="us-gaap_PlanNameAxis" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_ScheduleOfShareBasedCompensationArrangementsByShareBasedPaymentAwardTable" xlink:type="locator" xlink:label="us-gaap_ScheduleOfShareBasedCompensationArrangementsByShareBasedPaymentAwardTable" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardLineItems" xlink:type="locator" xlink:label="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardLineItems" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/all" xlink:from="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardLineItems" xlink:to="us-gaap_ScheduleOfShareBasedCompensationArrangementsByShareBasedPaymentAwardTable" order="10010.00" priority="2" use="optional" xbrldt:contextElement="segment" xbrldt:closed="true" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="us-gaap_ScheduleOfShareBasedCompensationArrangementsByShareBasedPaymentAwardTable" xlink:to="us-gaap_PlanNameAxis" order="10040.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="us-gaap_PlanNameAxis" xlink:to="us-gaap_PlanNameDomain_2" order="10050.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="us-gaap_PlanNameAxis" xlink:to="us-gaap_PlanNameDomain" order="10070.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_PlanNameDomain" xlink:to="zfgn_TwoThousandFourteenStockOptionMember" order="10090.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_PlanNameDomain" xlink:to="zfgn_GrantsOutsideOfTwoThousandFourteenPlanMember" order="10190.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="us-gaap_ScheduleOfShareBasedCompensationArrangementsByShareBasedPaymentAwardTable" xlink:to="us-gaap_AwardTypeAxis" order="10200.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="us-gaap_AwardTypeAxis" xlink:to="us-gaap_ShareBasedCompensationArrangementsByShareBasedPaymentAwardAwardTypeAndPlanNameDomain" order="10230.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ShareBasedCompensationArrangementsByShareBasedPaymentAwardAwardTypeAndPlanNameDomain" xlink:to="zfgn_TimeBasedVestingMember" order="10250.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="us-gaap_ScheduleOfShareBasedCompensationArrangementsByShareBasedPaymentAwardTable" xlink:to="srt_RangeAxis" order="10360.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="srt_RangeAxis" xlink:to="srt_RangeMember" order="10390.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="srt_RangeMember" xlink:to="srt_MinimumMember" order="10410.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="srt_RangeMember" xlink:to="srt_MaximumMember" order="10430.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="us-gaap_ScheduleOfShareBasedCompensationArrangementsByShareBasedPaymentAwardTable" xlink:to="us-gaap_TitleOfIndividualAxis" order="10760.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="us-gaap_TitleOfIndividualAxis" xlink:to="us-gaap_TitleOfIndividualWithRelationshipToEntityDomain_2" order="10770.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="us-gaap_TitleOfIndividualAxis" xlink:to="us-gaap_TitleOfIndividualWithRelationshipToEntityDomain" order="10790.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_TitleOfIndividualWithRelationshipToEntityDomain" xlink:to="zfgn_NonemployeeMember" order="10810.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ShareBasedCompensationArrangementsByShareBasedPaymentAwardAwardTypeAndPlanNameDomain" xlink:to="zfgn_MarketBasedVestingConditionsMember" order="10870.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_TitleOfIndividualWithRelationshipToEntityDomain" xlink:to="us-gaap_ChiefExecutiveOfficerMember" order="11110.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="us-gaap_ScheduleOfShareBasedCompensationArrangementsByShareBasedPaymentAwardTable" xlink:to="us-gaap_OptionIndexedToIssuersEquityTypeAxis" order="11320.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="us-gaap_OptionIndexedToIssuersEquityTypeAxis" xlink:to="us-gaap_OptionIndexedToIssuersEquityTypeDomain_2" order="11330.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="us-gaap_OptionIndexedToIssuersEquityTypeAxis" xlink:to="us-gaap_OptionIndexedToIssuersEquityTypeDomain" order="11350.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_OptionIndexedToIssuersEquityTypeDomain" xlink:to="us-gaap_EmployeeStockOptionMember" order="11370.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ShareBasedCompensationArrangementsByShareBasedPaymentAwardAwardTypeAndPlanNameDomain" xlink:to="us-gaap_RestrictedStockUnitsRSUMember" order="11710.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_PlanNameDomain" xlink:to="zfgn_TwoThousandAndFourteenEmployeeStockPurchasePlanMember" order="11830.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ShareBasedCompensationArrangementsByShareBasedPaymentAwardAwardTypeAndPlanNameDomain" xlink:to="zfgn_TimeBasedOptionsMember" order="12110.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ShareBasedCompensationArrangementsByShareBasedPaymentAwardAwardTypeAndPlanNameDomain" xlink:to="zfgn_MarketBasedStockOptionsMember" order="12190.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardLineItems" xlink:to="us-gaap_CommonStockCapitalSharesReservedForFutureIssuance" order="12240.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardLineItems" xlink:to="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardPercentageOfOutstandingStockMaximum" order="12260.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardLineItems" xlink:to="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfSharesAvailableForGrant" order="12280.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardLineItems" xlink:to="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsOtherIncreasesDecreasesInPeriod" order="12300.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardLineItems" xlink:to="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsGrantsInPeriodGross" order="12350.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardLineItems" xlink:to="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardAwardVestingPeriod1" order="12410.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardLineItems" xlink:to="us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardExpirationPeriod" order="12550.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardLineItems" xlink:to="us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardAwardVestingRightsPercentage" order="12610.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardLineItems" xlink:to="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardDescription" order="12670.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardLineItems" xlink:to="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsExercisesInPeriodTotalIntrinsicValue" order="12760.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardLineItems" xlink:to="us-gaap_ProceedsFromStockOptionsExercised" order="12850.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardLineItems" xlink:to="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsGrantsInPeriodWeightedAverageGrantDateFairValue" order="12940.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardLineItems" xlink:to="us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardOptionsNonvestedNumberOfShares" order="13030.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardLineItems" xlink:to="zfgn_ConsecutivePeriodOfMinimumCommonStockPriceDuringEarningPeriodDescription" order="13240.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardLineItems" xlink:to="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsForfeituresInPeriod" order="13380.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardLineItems" xlink:to="zfgn_ShareBasedCompensationArrangementByShareBasedPaymentAwardDateOfGrantedShareForfeited" order="13660.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardLineItems" xlink:to="zfgn_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsGrantTargetSharesPercentage" order="13830.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardLineItems" xlink:to="zfgn_ShareBasedCompensationArrangementByShareBasedPaymentAwardAggregateGrantDateFairValue" order="13920.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardLineItems" xlink:to="us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardOptionsVestedWeightedAverageGrantDateFairValue" order="13940.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardLineItems" xlink:to="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsOutstandingIntrinsicValue" order="13980.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardLineItems" xlink:to="us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardOptionsOutstandingWeightedAverageRemainingContractualTerm2" order="14000.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardLineItems" xlink:to="us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardEquityInstrumentsOtherThanOptionsAggregateIntrinsicValueVested" order="14050.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardLineItems" xlink:to="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardEquityInstrumentsOtherThanOptionsGrantsInPeriod" order="14110.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardLineItems" xlink:to="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardEquityInstrumentsOtherThanOptionsVestedInPeriodWeightedAverageGrantDateFairValue" order="14170.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardLineItems" xlink:to="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardEquityInstrumentsOtherThanOptionsNonvestedNumber" order="14230.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardLineItems" xlink:to="zfgn_FirstOfferingPeriodStartDate" order="14360.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardLineItems" xlink:to="zfgn_FirstOfferingPeriodEndDate" order="14400.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardLineItems" xlink:to="zfgn_SecondOfferingPeriodStartDate" order="14440.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardLineItems" xlink:to="zfgn_SecondOfferingPeriodEndDate" order="14480.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardLineItems" xlink:to="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardDiscountFromMarketPriceOfferingDate" order="14520.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardLineItems" xlink:to="us-gaap_StockIssuedDuringPeriodSharesShareBasedCompensation" order="14560.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardLineItems" xlink:to="us-gaap_StockOptionPlanExpense" order="14670.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardLineItems" xlink:to="us-gaap_EmployeeServiceShareBasedCompensationNonvestedAwardsTotalCompensationCostNotYetRecognized" order="14720.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardLineItems" xlink:to="us-gaap_EmployeeServiceShareBasedCompensationNonvestedAwardsTotalCompensationCostNotYetRecognizedPeriodForRecognition1" order="14740.00" priority="2" use="optional" />
  </definitionLink>
  <roleRef roleURI="http://www.zafgen.com/20181231/taxonomy/role/DisclosureStockBasedAwardsAssumptionsUsedToDetermineFairValueOfStockOptionsGrantedDetail" xlink:href="zfgn-20181231.xsd#Role_DisclosureStockBasedAwardsAssumptionsUsedToDetermineFairValueOfStockOptionsGrantedDetail" xlink:type="simple" />
  <definitionLink xlink:type="extended" xlink:role="http://www.zafgen.com/20181231/taxonomy/role/DisclosureStockBasedAwardsAssumptionsUsedToDetermineFairValueOfStockOptionsGrantedDetail">
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardFairValueAssumptionsExpectedDividendRate" xlink:type="locator" xlink:label="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardFairValueAssumptionsExpectedDividendRate" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardFairValueAssumptionsExpectedVolatilityRate" xlink:type="locator" xlink:label="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardFairValueAssumptionsExpectedVolatilityRate" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardFairValueAssumptionsExpectedTerm1" xlink:type="locator" xlink:label="us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardFairValueAssumptionsExpectedTerm1" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardFairValueAssumptionsRiskFreeInterestRate" xlink:type="locator" xlink:label="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardFairValueAssumptionsRiskFreeInterestRate" />
    <loc xlink:href="zfgn-20181231.xsd#zfgn_MarketBasedVestingConditionsMember" xlink:type="locator" xlink:label="zfgn_MarketBasedVestingConditionsMember" />
    <loc xlink:href="zfgn-20181231.xsd#zfgn_TimeBasedVestingMember" xlink:type="locator" xlink:label="zfgn_TimeBasedVestingMember" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_ShareBasedCompensationArrangementsByShareBasedPaymentAwardAwardTypeAndPlanNameDomain" xlink:type="locator" xlink:label="us-gaap_ShareBasedCompensationArrangementsByShareBasedPaymentAwardAwardTypeAndPlanNameDomain" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_AwardTypeAxis" xlink:type="locator" xlink:label="us-gaap_AwardTypeAxis" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_ScheduleOfShareBasedCompensationArrangementsByShareBasedPaymentAwardTable" xlink:type="locator" xlink:label="us-gaap_ScheduleOfShareBasedCompensationArrangementsByShareBasedPaymentAwardTable" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardLineItems" xlink:type="locator" xlink:label="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardLineItems" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/all" xlink:from="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardLineItems" xlink:to="us-gaap_ScheduleOfShareBasedCompensationArrangementsByShareBasedPaymentAwardTable" order="10010.00" priority="2" use="optional" xbrldt:contextElement="segment" xbrldt:closed="true" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="us-gaap_ScheduleOfShareBasedCompensationArrangementsByShareBasedPaymentAwardTable" xlink:to="us-gaap_AwardTypeAxis" order="10040.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="us-gaap_AwardTypeAxis" xlink:to="us-gaap_ShareBasedCompensationArrangementsByShareBasedPaymentAwardAwardTypeAndPlanNameDomain" order="10070.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ShareBasedCompensationArrangementsByShareBasedPaymentAwardAwardTypeAndPlanNameDomain" xlink:to="zfgn_TimeBasedVestingMember" order="10090.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ShareBasedCompensationArrangementsByShareBasedPaymentAwardAwardTypeAndPlanNameDomain" xlink:to="zfgn_MarketBasedVestingConditionsMember" order="10190.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardLineItems" xlink:to="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardFairValueAssumptionsRiskFreeInterestRate" order="10280.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardLineItems" xlink:to="us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardFairValueAssumptionsExpectedTerm1" order="10340.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardLineItems" xlink:to="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardFairValueAssumptionsExpectedVolatilityRate" order="10400.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardLineItems" xlink:to="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardFairValueAssumptionsExpectedDividendRate" order="10460.00" priority="2" use="optional" />
  </definitionLink>
  <roleRef roleURI="http://www.zafgen.com/20181231/taxonomy/role/DisclosureStockBasedAwardsSummaryOfStockOptionActivityDetail" xlink:href="zfgn-20181231.xsd#Role_DisclosureStockBasedAwardsSummaryOfStockOptionActivityDetail" xlink:type="simple" />
  <definitionLink xlink:type="extended" xlink:role="http://www.zafgen.com/20181231/taxonomy/role/DisclosureStockBasedAwardsSummaryOfStockOptionActivityDetail">
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardOptionsExercisableIntrinsicValue1" xlink:type="locator" xlink:label="us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardOptionsExercisableIntrinsicValue1" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsOutstandingIntrinsicValue" xlink:type="locator" xlink:label="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsOutstandingIntrinsicValue" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardOptionsExercisableWeightedAverageRemainingContractualTerm1" xlink:type="locator" xlink:label="us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardOptionsExercisableWeightedAverageRemainingContractualTerm1" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardOptionsOutstandingWeightedAverageRemainingContractualTerm2" xlink:type="locator" xlink:label="us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardOptionsOutstandingWeightedAverageRemainingContractualTerm2" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsExercisableWeightedAverageExercisePrice" xlink:type="locator" xlink:label="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsExercisableWeightedAverageExercisePrice" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_ShareBasedCompensationArrangementsByShareBasedPaymentAwardOptionsForfeituresInPeriodWeightedAverageExercisePrice" xlink:type="locator" xlink:label="us-gaap_ShareBasedCompensationArrangementsByShareBasedPaymentAwardOptionsForfeituresInPeriodWeightedAverageExercisePrice" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_ShareBasedCompensationArrangementsByShareBasedPaymentAwardOptionsExercisesInPeriodWeightedAverageExercisePrice" xlink:type="locator" xlink:label="us-gaap_ShareBasedCompensationArrangementsByShareBasedPaymentAwardOptionsExercisesInPeriodWeightedAverageExercisePrice" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_ShareBasedCompensationArrangementsByShareBasedPaymentAwardOptionsGrantsInPeriodWeightedAverageExercisePrice" xlink:type="locator" xlink:label="us-gaap_ShareBasedCompensationArrangementsByShareBasedPaymentAwardOptionsGrantsInPeriodWeightedAverageExercisePrice" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsOutstandingWeightedAverageExercisePrice" xlink:type="locator" xlink:label="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsOutstandingWeightedAverageExercisePrice" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsExercisableNumber" xlink:type="locator" xlink:label="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsExercisableNumber" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsForfeituresInPeriod" xlink:type="locator" xlink:label="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsForfeituresInPeriod" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_StockIssuedDuringPeriodSharesStockOptionsExercised" xlink:type="locator" xlink:label="us-gaap_StockIssuedDuringPeriodSharesStockOptionsExercised" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsGrantsInPeriodGross" xlink:type="locator" xlink:label="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsGrantsInPeriodGross" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsOutstandingNumber" xlink:type="locator" xlink:label="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsOutstandingNumber" />
    <loc xlink:href="zfgn-20181231.xsd#zfgn_TimeBasedVestingMember" xlink:type="locator" xlink:label="zfgn_TimeBasedVestingMember" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_ShareBasedCompensationArrangementsByShareBasedPaymentAwardAwardTypeAndPlanNameDomain" xlink:type="locator" xlink:label="us-gaap_ShareBasedCompensationArrangementsByShareBasedPaymentAwardAwardTypeAndPlanNameDomain" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_AwardTypeAxis" xlink:type="locator" xlink:label="us-gaap_AwardTypeAxis" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_ScheduleOfShareBasedCompensationArrangementsByShareBasedPaymentAwardTable" xlink:type="locator" xlink:label="us-gaap_ScheduleOfShareBasedCompensationArrangementsByShareBasedPaymentAwardTable" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardLineItems" xlink:type="locator" xlink:label="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardLineItems" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/all" xlink:from="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardLineItems" xlink:to="us-gaap_ScheduleOfShareBasedCompensationArrangementsByShareBasedPaymentAwardTable" order="10010.00" priority="2" use="optional" xbrldt:contextElement="segment" xbrldt:closed="true" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="us-gaap_ScheduleOfShareBasedCompensationArrangementsByShareBasedPaymentAwardTable" xlink:to="us-gaap_AwardTypeAxis" order="10040.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="us-gaap_AwardTypeAxis" xlink:to="us-gaap_ShareBasedCompensationArrangementsByShareBasedPaymentAwardAwardTypeAndPlanNameDomain" order="10070.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ShareBasedCompensationArrangementsByShareBasedPaymentAwardAwardTypeAndPlanNameDomain" xlink:to="zfgn_TimeBasedVestingMember" order="10090.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardLineItems" xlink:to="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsOutstandingNumber" order="10300.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardLineItems" xlink:to="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsGrantsInPeriodGross" order="10400.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardLineItems" xlink:to="us-gaap_StockIssuedDuringPeriodSharesStockOptionsExercised" order="10500.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardLineItems" xlink:to="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsForfeituresInPeriod" order="10600.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardLineItems" xlink:to="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsExercisableNumber" order="10800.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardLineItems" xlink:to="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsOutstandingWeightedAverageExercisePrice" order="10930.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardLineItems" xlink:to="us-gaap_ShareBasedCompensationArrangementsByShareBasedPaymentAwardOptionsGrantsInPeriodWeightedAverageExercisePrice" order="11030.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardLineItems" xlink:to="us-gaap_ShareBasedCompensationArrangementsByShareBasedPaymentAwardOptionsExercisesInPeriodWeightedAverageExercisePrice" order="11130.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardLineItems" xlink:to="us-gaap_ShareBasedCompensationArrangementsByShareBasedPaymentAwardOptionsForfeituresInPeriodWeightedAverageExercisePrice" order="11230.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardLineItems" xlink:to="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsExercisableWeightedAverageExercisePrice" order="11430.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardLineItems" xlink:to="us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardOptionsOutstandingWeightedAverageRemainingContractualTerm2" order="11560.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardLineItems" xlink:to="us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardOptionsExercisableWeightedAverageRemainingContractualTerm1" order="11760.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardLineItems" xlink:to="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsOutstandingIntrinsicValue" order="11890.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardLineItems" xlink:to="us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardOptionsExercisableIntrinsicValue1" order="12090.00" priority="2" use="optional" />
  </definitionLink>
  <roleRef roleURI="http://www.zafgen.com/20181231/taxonomy/role/DisclosureStockBasedAwardsSummaryOfStockBasedCompensationExpenseRelatedToStockOptionsAndRestrictedCommonStockDetail" xlink:href="zfgn-20181231.xsd#Role_DisclosureStockBasedAwardsSummaryOfStockBasedCompensationExpenseRelatedToStockOptionsAndRestrictedCommonStockDetail" xlink:type="simple" />
  <definitionLink xlink:type="extended" xlink:role="http://www.zafgen.com/20181231/taxonomy/role/DisclosureStockBasedAwardsSummaryOfStockBasedCompensationExpenseRelatedToStockOptionsAndRestrictedCommonStockDetail">
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_AllocatedShareBasedCompensationExpense" xlink:type="locator" xlink:label="us-gaap_AllocatedShareBasedCompensationExpense" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_GeneralAndAdministrativeExpenseMember" xlink:type="locator" xlink:label="us-gaap_GeneralAndAdministrativeExpenseMember" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_ResearchAndDevelopmentExpenseMember" xlink:type="locator" xlink:label="us-gaap_ResearchAndDevelopmentExpenseMember" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_IncomeStatementLocationDomain" xlink:type="locator" xlink:label="us-gaap_IncomeStatementLocationDomain" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_IncomeStatementLocationDomain" xlink:type="locator" xlink:label="us-gaap_IncomeStatementLocationDomain_2" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_IncomeStatementLocationAxis" xlink:type="locator" xlink:label="us-gaap_IncomeStatementLocationAxis" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_ScheduleOfShareBasedCompensationArrangementsByShareBasedPaymentAwardTable" xlink:type="locator" xlink:label="us-gaap_ScheduleOfShareBasedCompensationArrangementsByShareBasedPaymentAwardTable" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardLineItems" xlink:type="locator" xlink:label="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardLineItems" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/all" xlink:from="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardLineItems" xlink:to="us-gaap_ScheduleOfShareBasedCompensationArrangementsByShareBasedPaymentAwardTable" order="10010.00" priority="2" use="optional" xbrldt:contextElement="segment" xbrldt:closed="true" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="us-gaap_ScheduleOfShareBasedCompensationArrangementsByShareBasedPaymentAwardTable" xlink:to="us-gaap_IncomeStatementLocationAxis" order="10040.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="us-gaap_IncomeStatementLocationAxis" xlink:to="us-gaap_IncomeStatementLocationDomain_2" order="10050.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="us-gaap_IncomeStatementLocationAxis" xlink:to="us-gaap_IncomeStatementLocationDomain" order="10070.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_IncomeStatementLocationDomain" xlink:to="us-gaap_ResearchAndDevelopmentExpenseMember" order="10090.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_IncomeStatementLocationDomain" xlink:to="us-gaap_GeneralAndAdministrativeExpenseMember" order="10110.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardLineItems" xlink:to="us-gaap_AllocatedShareBasedCompensationExpense" order="10140.00" priority="2" use="optional" />
  </definitionLink>
  <roleRef roleURI="http://www.zafgen.com/20181231/taxonomy/role/DisclosureNetLossPerShareSummaryOfCommonStockEquivalentsOutstandingDetail" xlink:href="zfgn-20181231.xsd#Role_DisclosureNetLossPerShareSummaryOfCommonStockEquivalentsOutstandingDetail" xlink:type="simple" />
  <definitionLink xlink:type="extended" xlink:role="http://www.zafgen.com/20181231/taxonomy/role/DisclosureNetLossPerShareSummaryOfCommonStockEquivalentsOutstandingDetail">
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_AntidilutiveSecuritiesExcludedFromComputationOfEarningsPerShareAmount" xlink:type="locator" xlink:label="us-gaap_AntidilutiveSecuritiesExcludedFromComputationOfEarningsPerShareAmount" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_EmployeeStockOptionMember" xlink:type="locator" xlink:label="us-gaap_EmployeeStockOptionMember" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_AntidilutiveSecuritiesNameDomain" xlink:type="locator" xlink:label="us-gaap_AntidilutiveSecuritiesNameDomain" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_AntidilutiveSecuritiesNameDomain" xlink:type="locator" xlink:label="us-gaap_AntidilutiveSecuritiesNameDomain_2" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_AntidilutiveSecuritiesExcludedFromComputationOfEarningsPerShareByAntidilutiveSecuritiesAxis" xlink:type="locator" xlink:label="us-gaap_AntidilutiveSecuritiesExcludedFromComputationOfEarningsPerShareByAntidilutiveSecuritiesAxis" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_ScheduleOfAntidilutiveSecuritiesExcludedFromComputationOfEarningsPerShareTable" xlink:type="locator" xlink:label="us-gaap_ScheduleOfAntidilutiveSecuritiesExcludedFromComputationOfEarningsPerShareTable" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_AntidilutiveSecuritiesExcludedFromComputationOfEarningsPerShareLineItems" xlink:type="locator" xlink:label="us-gaap_AntidilutiveSecuritiesExcludedFromComputationOfEarningsPerShareLineItems" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/all" xlink:from="us-gaap_AntidilutiveSecuritiesExcludedFromComputationOfEarningsPerShareLineItems" xlink:to="us-gaap_ScheduleOfAntidilutiveSecuritiesExcludedFromComputationOfEarningsPerShareTable" order="10010.00" priority="2" use="optional" xbrldt:contextElement="segment" xbrldt:closed="true" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="us-gaap_ScheduleOfAntidilutiveSecuritiesExcludedFromComputationOfEarningsPerShareTable" xlink:to="us-gaap_AntidilutiveSecuritiesExcludedFromComputationOfEarningsPerShareByAntidilutiveSecuritiesAxis" order="10040.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="us-gaap_AntidilutiveSecuritiesExcludedFromComputationOfEarningsPerShareByAntidilutiveSecuritiesAxis" xlink:to="us-gaap_AntidilutiveSecuritiesNameDomain_2" order="10050.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="us-gaap_AntidilutiveSecuritiesExcludedFromComputationOfEarningsPerShareByAntidilutiveSecuritiesAxis" xlink:to="us-gaap_AntidilutiveSecuritiesNameDomain" order="10070.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_AntidilutiveSecuritiesNameDomain" xlink:to="us-gaap_EmployeeStockOptionMember" order="10090.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_AntidilutiveSecuritiesExcludedFromComputationOfEarningsPerShareLineItems" xlink:to="us-gaap_AntidilutiveSecuritiesExcludedFromComputationOfEarningsPerShareAmount" order="10120.00" priority="2" use="optional" />
  </definitionLink>
  <roleRef roleURI="http://www.zafgen.com/20181231/taxonomy/role/DisclosureCommitmentsAndContingenciesAdditionalInformationDetail" xlink:href="zfgn-20181231.xsd#Role_DisclosureCommitmentsAndContingenciesAdditionalInformationDetail" xlink:type="simple" />
  <definitionLink xlink:type="extended" xlink:role="http://www.zafgen.com/20181231/taxonomy/role/DisclosureCommitmentsAndContingenciesAdditionalInformationDetail">
    <loc xlink:href="zfgn-20181231.xsd#zfgn_MilestoneLiability" xlink:type="locator" xlink:label="zfgn_MilestoneLiability" />
    <loc xlink:href="zfgn-20181231.xsd#zfgn_LicensingFeesPerProductMaximum" xlink:type="locator" xlink:label="zfgn_LicensingFeesPerProductMaximum" />
    <loc xlink:href="zfgn-20181231.xsd#zfgn_MilestonePaymentAmount" xlink:type="locator" xlink:label="zfgn_MilestonePaymentAmount" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_OperatingLeasesRentExpenseNet" xlink:type="locator" xlink:label="us-gaap_OperatingLeasesRentExpenseNet" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_OperatingLeasesRentExpenseSubleaseRentals1" xlink:type="locator" xlink:label="us-gaap_OperatingLeasesRentExpenseSubleaseRentals1" />
    <loc xlink:href="zfgn-20181231.xsd#zfgn_SubleaseExpirationDate" xlink:type="locator" xlink:label="zfgn_SubleaseExpirationDate" />
    <loc xlink:href="zfgn-20181231.xsd#zfgn_SubleaseAreaOfRealEstateProperty" xlink:type="locator" xlink:label="zfgn_SubleaseAreaOfRealEstateProperty" />
    <loc xlink:href="zfgn-20181231.xsd#zfgn_OperatingLeasesNumberOfOptionsToExtendLease" xlink:type="locator" xlink:label="zfgn_OperatingLeasesNumberOfOptionsToExtendLease" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_LesseeOperatingLeaseRenewalTerm" xlink:type="locator" xlink:label="us-gaap_LesseeOperatingLeaseRenewalTerm" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_LeaseExpirationDate1" xlink:type="locator" xlink:label="us-gaap_LeaseExpirationDate1" />
    <loc xlink:href="zfgn-20181231.xsd#zfgn_DevelopmentBasedMilestonesMember" xlink:type="locator" xlink:label="zfgn_DevelopmentBasedMilestonesMember" />
    <loc xlink:href="zfgn-20181231.xsd#zfgn_SubsequentLicensedProductMember" xlink:type="locator" xlink:label="zfgn_SubsequentLicensedProductMember" />
    <loc xlink:href="zfgn-20181231.xsd#zfgn_ProductCommercializationMilestonesMember" xlink:type="locator" xlink:label="zfgn_ProductCommercializationMilestonesMember" />
    <loc xlink:href="zfgn-20181231.xsd#zfgn_PreCommercializationMilestonesMember" xlink:type="locator" xlink:label="zfgn_PreCommercializationMilestonesMember" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_LongTermPurchaseCommitmentCategoryOfItemPurchasedDomain" xlink:type="locator" xlink:label="us-gaap_LongTermPurchaseCommitmentCategoryOfItemPurchasedDomain" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_LongTermPurchaseCommitmentCategoryOfItemPurchasedDomain" xlink:type="locator" xlink:label="us-gaap_LongTermPurchaseCommitmentCategoryOfItemPurchasedDomain_2" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_LongTermPurchaseCommitmentByCategoryOfItemPurchasedAxis" xlink:type="locator" xlink:label="us-gaap_LongTermPurchaseCommitmentByCategoryOfItemPurchasedAxis" />
    <loc xlink:href="http://xbrl.fasb.org/srt/2018/elts/srt-2018-01-31.xsd#srt_MinimumMember" xlink:type="locator" xlink:label="srt_MinimumMember" />
    <loc xlink:href="http://xbrl.fasb.org/srt/2018/elts/srt-2018-01-31.xsd#srt_MaximumMember" xlink:type="locator" xlink:label="srt_MaximumMember" />
    <loc xlink:href="http://xbrl.fasb.org/srt/2018/elts/srt-2018-01-31.xsd#srt_RangeMember" xlink:type="locator" xlink:label="srt_RangeMember" />
    <loc xlink:href="http://xbrl.fasb.org/srt/2018/elts/srt-2018-01-31.xsd#srt_RangeAxis" xlink:type="locator" xlink:label="srt_RangeAxis" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_ScenarioForecastMember" xlink:type="locator" xlink:label="us-gaap_ScenarioForecastMember" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_ScenarioUnspecifiedDomain" xlink:type="locator" xlink:label="us-gaap_ScenarioUnspecifiedDomain" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_ScenarioUnspecifiedDomain" xlink:type="locator" xlink:label="us-gaap_ScenarioUnspecifiedDomain_2" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_StatementScenarioAxis" xlink:type="locator" xlink:label="us-gaap_StatementScenarioAxis" />
    <loc xlink:href="zfgn-20181231.xsd#zfgn_UnrelatedThirdPartyMember" xlink:type="locator" xlink:label="zfgn_UnrelatedThirdPartyMember" />
    <loc xlink:href="http://xbrl.fasb.org/srt/2018/elts/srt-2018-01-31.xsd#srt_RepurchaseAgreementCounterpartyNameDomain" xlink:type="locator" xlink:label="srt_RepurchaseAgreementCounterpartyNameDomain" />
    <loc xlink:href="http://xbrl.fasb.org/srt/2018/elts/srt-2018-01-31.xsd#srt_RepurchaseAgreementCounterpartyNameDomain" xlink:type="locator" xlink:label="srt_RepurchaseAgreementCounterpartyNameDomain_2" />
    <loc xlink:href="http://xbrl.fasb.org/srt/2018/elts/srt-2018-01-31.xsd#srt_CounterpartyNameAxis" xlink:type="locator" xlink:label="srt_CounterpartyNameAxis" />
    <loc xlink:href="zfgn-20181231.xsd#zfgn_AdditionalOfficeSpaceTwoMember" xlink:type="locator" xlink:label="zfgn_AdditionalOfficeSpaceTwoMember" />
    <loc xlink:href="zfgn-20181231.xsd#zfgn_AdditionalOfficeSpaceMember" xlink:type="locator" xlink:label="zfgn_AdditionalOfficeSpaceMember" />
    <loc xlink:href="zfgn-20181231.xsd#zfgn_OfficeSpaceLeaseMember" xlink:type="locator" xlink:label="zfgn_OfficeSpaceLeaseMember" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_LeaseArrangementTypeDomain" xlink:type="locator" xlink:label="us-gaap_LeaseArrangementTypeDomain" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_LeaseArrangementTypeDomain" xlink:type="locator" xlink:label="us-gaap_LeaseArrangementTypeDomain_2" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_LeaseArrangementTypeAxis" xlink:type="locator" xlink:label="us-gaap_LeaseArrangementTypeAxis" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_OtherCommitmentsTable" xlink:type="locator" xlink:label="us-gaap_OtherCommitmentsTable" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_OtherCommitmentsLineItems" xlink:type="locator" xlink:label="us-gaap_OtherCommitmentsLineItems" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/all" xlink:from="us-gaap_OtherCommitmentsLineItems" xlink:to="us-gaap_OtherCommitmentsTable" order="10010.00" priority="2" use="optional" xbrldt:contextElement="segment" xbrldt:closed="true" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="us-gaap_OtherCommitmentsTable" xlink:to="us-gaap_LeaseArrangementTypeAxis" order="10040.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="us-gaap_LeaseArrangementTypeAxis" xlink:to="us-gaap_LeaseArrangementTypeDomain_2" order="10050.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="us-gaap_LeaseArrangementTypeAxis" xlink:to="us-gaap_LeaseArrangementTypeDomain" order="10070.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_LeaseArrangementTypeDomain" xlink:to="zfgn_OfficeSpaceLeaseMember" order="10090.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_LeaseArrangementTypeDomain" xlink:to="zfgn_AdditionalOfficeSpaceMember" order="10130.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_LeaseArrangementTypeDomain" xlink:to="zfgn_AdditionalOfficeSpaceTwoMember" order="10270.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="us-gaap_OtherCommitmentsTable" xlink:to="srt_CounterpartyNameAxis" order="10300.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="srt_CounterpartyNameAxis" xlink:to="srt_RepurchaseAgreementCounterpartyNameDomain_2" order="10310.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="srt_CounterpartyNameAxis" xlink:to="srt_RepurchaseAgreementCounterpartyNameDomain" order="10330.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="srt_RepurchaseAgreementCounterpartyNameDomain" xlink:to="zfgn_UnrelatedThirdPartyMember" order="10350.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="us-gaap_OtherCommitmentsTable" xlink:to="us-gaap_StatementScenarioAxis" order="10400.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="us-gaap_StatementScenarioAxis" xlink:to="us-gaap_ScenarioUnspecifiedDomain_2" order="10410.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="us-gaap_StatementScenarioAxis" xlink:to="us-gaap_ScenarioUnspecifiedDomain" order="10430.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ScenarioUnspecifiedDomain" xlink:to="us-gaap_ScenarioForecastMember" order="10450.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="us-gaap_OtherCommitmentsTable" xlink:to="srt_RangeAxis" order="10460.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="srt_RangeAxis" xlink:to="srt_RangeMember" order="10490.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="srt_RangeMember" xlink:to="srt_MaximumMember" order="10510.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="srt_RangeMember" xlink:to="srt_MinimumMember" order="10550.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="us-gaap_OtherCommitmentsTable" xlink:to="us-gaap_LongTermPurchaseCommitmentByCategoryOfItemPurchasedAxis" order="10560.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="us-gaap_LongTermPurchaseCommitmentByCategoryOfItemPurchasedAxis" xlink:to="us-gaap_LongTermPurchaseCommitmentCategoryOfItemPurchasedDomain_2" order="10570.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="us-gaap_LongTermPurchaseCommitmentByCategoryOfItemPurchasedAxis" xlink:to="us-gaap_LongTermPurchaseCommitmentCategoryOfItemPurchasedDomain" order="10590.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_LongTermPurchaseCommitmentCategoryOfItemPurchasedDomain" xlink:to="zfgn_PreCommercializationMilestonesMember" order="10610.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_LongTermPurchaseCommitmentCategoryOfItemPurchasedDomain" xlink:to="zfgn_ProductCommercializationMilestonesMember" order="10630.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_LongTermPurchaseCommitmentCategoryOfItemPurchasedDomain" xlink:to="zfgn_SubsequentLicensedProductMember" order="10650.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_LongTermPurchaseCommitmentCategoryOfItemPurchasedDomain" xlink:to="zfgn_DevelopmentBasedMilestonesMember" order="10710.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_OtherCommitmentsLineItems" xlink:to="us-gaap_LeaseExpirationDate1" order="10740.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_OtherCommitmentsLineItems" xlink:to="us-gaap_LesseeOperatingLeaseRenewalTerm" order="10900.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_OtherCommitmentsLineItems" xlink:to="zfgn_OperatingLeasesNumberOfOptionsToExtendLease" order="10940.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_OtherCommitmentsLineItems" xlink:to="zfgn_SubleaseAreaOfRealEstateProperty" order="10980.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_OtherCommitmentsLineItems" xlink:to="zfgn_SubleaseExpirationDate" order="11020.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_OtherCommitmentsLineItems" xlink:to="us-gaap_OperatingLeasesRentExpenseSubleaseRentals1" order="11060.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_OtherCommitmentsLineItems" xlink:to="us-gaap_OperatingLeasesRentExpenseNet" order="11210.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_OtherCommitmentsLineItems" xlink:to="zfgn_MilestonePaymentAmount" order="11300.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_OtherCommitmentsLineItems" xlink:to="zfgn_LicensingFeesPerProductMaximum" order="11340.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_OtherCommitmentsLineItems" xlink:to="zfgn_MilestoneLiability" order="11390.00" priority="2" use="optional" />
  </definitionLink>
  <roleRef roleURI="http://www.zafgen.com/20181231/taxonomy/role/DisclosureIncomeTaxesAdditionalInformationDetail" xlink:href="zfgn-20181231.xsd#Role_DisclosureIncomeTaxesAdditionalInformationDetail" xlink:type="simple" />
  <definitionLink xlink:type="extended" xlink:role="http://www.zafgen.com/20181231/taxonomy/role/DisclosureIncomeTaxesAdditionalInformationDetail">
    <loc xlink:href="zfgn-20181231.xsd#zfgn_TaxCutsAndJobsActOf2017ChangeInTaxRateIncomeTaxExpenseBenefit" xlink:type="locator" xlink:label="zfgn_TaxCutsAndJobsActOf2017ChangeInTaxRateIncomeTaxExpenseBenefit" />
    <loc xlink:href="zfgn-20181231.xsd#zfgn_TaxCutsAndJobsActOf2017IncompleteAccountingChangeInTaxRateDeferredTaxLiabilityProvisionalIncomeTaxBenefit" xlink:type="locator" xlink:label="zfgn_TaxCutsAndJobsActOf2017IncompleteAccountingChangeInTaxRateDeferredTaxLiabilityProvisionalIncomeTaxBenefit" />
    <loc xlink:href="zfgn-20181231.xsd#zfgn_TaxCutsAndJobsActOf2017NetOperatingLossesCarryforwardMaximumPercentageOfTaxableIncome" xlink:type="locator" xlink:label="zfgn_TaxCutsAndJobsActOf2017NetOperatingLossesCarryforwardMaximumPercentageOfTaxableIncome" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_EffectiveIncomeTaxRateReconciliationAtFederalStatutoryIncomeTaxRate" xlink:type="locator" xlink:label="us-gaap_EffectiveIncomeTaxRateReconciliationAtFederalStatutoryIncomeTaxRate" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_UnrecognizedTaxBenefits" xlink:type="locator" xlink:label="us-gaap_UnrecognizedTaxBenefits" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_DeferredTaxAssetsGross" xlink:type="locator" xlink:label="us-gaap_DeferredTaxAssetsGross" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_LiabilityForUncertainTaxPositionsCurrent" xlink:type="locator" xlink:label="us-gaap_LiabilityForUncertainTaxPositionsCurrent" />
    <loc xlink:href="zfgn-20181231.xsd#zfgn_TaxCreditCarryForwardExpirationYearStart" xlink:type="locator" xlink:label="zfgn_TaxCreditCarryForwardExpirationYearStart" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_DeferredTaxAssetsOperatingLossCarryforwardsStateAndLocal" xlink:type="locator" xlink:label="us-gaap_DeferredTaxAssetsOperatingLossCarryforwardsStateAndLocal" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_DeferredTaxAssetsOperatingLossCarryforwardsDomestic" xlink:type="locator" xlink:label="us-gaap_DeferredTaxAssetsOperatingLossCarryforwardsDomestic" />
    <loc xlink:href="zfgn-20181231.xsd#zfgn_NetOperatingLossCarryForwardExpirationYearBegin" xlink:type="locator" xlink:label="zfgn_NetOperatingLossCarryForwardExpirationYearBegin" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_OperatingLossCarryforwards" xlink:type="locator" xlink:label="us-gaap_OperatingLossCarryforwards" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_IncomeTaxExpenseBenefit" xlink:type="locator" xlink:label="us-gaap_IncomeTaxExpenseBenefit" />
    <loc xlink:href="http://xbrl.fasb.org/srt/2018/elts/srt-2018-01-31.xsd#srt_MinimumMember" xlink:type="locator" xlink:label="srt_MinimumMember" />
    <loc xlink:href="http://xbrl.fasb.org/srt/2018/elts/srt-2018-01-31.xsd#srt_MaximumMember" xlink:type="locator" xlink:label="srt_MaximumMember" />
    <loc xlink:href="http://xbrl.fasb.org/srt/2018/elts/srt-2018-01-31.xsd#srt_RangeMember" xlink:type="locator" xlink:label="srt_RangeMember" />
    <loc xlink:href="http://xbrl.fasb.org/srt/2018/elts/srt-2018-01-31.xsd#srt_RangeAxis" xlink:type="locator" xlink:label="srt_RangeAxis" />
    <loc xlink:href="zfgn-20181231.xsd#zfgn_NoExpirationMember" xlink:type="locator" xlink:label="zfgn_NoExpirationMember" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_TaxPeriodDomain" xlink:type="locator" xlink:label="us-gaap_TaxPeriodDomain" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_TaxPeriodDomain" xlink:type="locator" xlink:label="us-gaap_TaxPeriodDomain_2" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_TaxPeriodAxis" xlink:type="locator" xlink:label="us-gaap_TaxPeriodAxis" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_StateAndLocalJurisdictionMember" xlink:type="locator" xlink:label="us-gaap_StateAndLocalJurisdictionMember" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_DomesticCountryMember" xlink:type="locator" xlink:label="us-gaap_DomesticCountryMember" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_IncomeTaxAuthorityDomain" xlink:type="locator" xlink:label="us-gaap_IncomeTaxAuthorityDomain" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_IncomeTaxAuthorityDomain" xlink:type="locator" xlink:label="us-gaap_IncomeTaxAuthorityDomain_2" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_IncomeTaxAuthorityAxis" xlink:type="locator" xlink:label="us-gaap_IncomeTaxAuthorityAxis" />
    <loc xlink:href="zfgn-20181231.xsd#zfgn_IncomeTaxesDisclosureTable" xlink:type="locator" xlink:label="zfgn_IncomeTaxesDisclosureTable" />
    <loc xlink:href="zfgn-20181231.xsd#zfgn_IncomeTaxesDisclosureLineItems" xlink:type="locator" xlink:label="zfgn_IncomeTaxesDisclosureLineItems" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/all" xlink:from="zfgn_IncomeTaxesDisclosureLineItems" xlink:to="zfgn_IncomeTaxesDisclosureTable" order="10010.00" priority="2" use="optional" xbrldt:contextElement="segment" xbrldt:closed="true" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="zfgn_IncomeTaxesDisclosureTable" xlink:to="us-gaap_IncomeTaxAuthorityAxis" order="10040.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="us-gaap_IncomeTaxAuthorityAxis" xlink:to="us-gaap_IncomeTaxAuthorityDomain_2" order="10050.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="us-gaap_IncomeTaxAuthorityAxis" xlink:to="us-gaap_IncomeTaxAuthorityDomain" order="10070.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_IncomeTaxAuthorityDomain" xlink:to="us-gaap_DomesticCountryMember" order="10090.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_IncomeTaxAuthorityDomain" xlink:to="us-gaap_StateAndLocalJurisdictionMember" order="10110.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="zfgn_IncomeTaxesDisclosureTable" xlink:to="us-gaap_TaxPeriodAxis" order="10200.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="us-gaap_TaxPeriodAxis" xlink:to="us-gaap_TaxPeriodDomain_2" order="10210.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="us-gaap_TaxPeriodAxis" xlink:to="us-gaap_TaxPeriodDomain" order="10230.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_TaxPeriodDomain" xlink:to="zfgn_NoExpirationMember" order="10250.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="zfgn_IncomeTaxesDisclosureTable" xlink:to="srt_RangeAxis" order="10260.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="srt_RangeAxis" xlink:to="srt_RangeMember" order="10290.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="srt_RangeMember" xlink:to="srt_MaximumMember" order="10310.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="srt_RangeMember" xlink:to="srt_MinimumMember" order="10330.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="zfgn_IncomeTaxesDisclosureLineItems" xlink:to="us-gaap_IncomeTaxExpenseBenefit" order="10360.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="zfgn_IncomeTaxesDisclosureLineItems" xlink:to="us-gaap_OperatingLossCarryforwards" order="10450.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="zfgn_IncomeTaxesDisclosureLineItems" xlink:to="zfgn_NetOperatingLossCarryForwardExpirationYearBegin" order="10490.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="zfgn_IncomeTaxesDisclosureLineItems" xlink:to="us-gaap_DeferredTaxAssetsOperatingLossCarryforwardsDomestic" order="10550.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="zfgn_IncomeTaxesDisclosureLineItems" xlink:to="us-gaap_DeferredTaxAssetsOperatingLossCarryforwardsStateAndLocal" order="10570.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="zfgn_IncomeTaxesDisclosureLineItems" xlink:to="zfgn_TaxCreditCarryForwardExpirationYearStart" order="10590.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="zfgn_IncomeTaxesDisclosureLineItems" xlink:to="us-gaap_LiabilityForUncertainTaxPositionsCurrent" order="10660.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="zfgn_IncomeTaxesDisclosureLineItems" xlink:to="us-gaap_DeferredTaxAssetsGross" order="10710.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="zfgn_IncomeTaxesDisclosureLineItems" xlink:to="us-gaap_UnrecognizedTaxBenefits" order="10780.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="zfgn_IncomeTaxesDisclosureLineItems" xlink:to="us-gaap_EffectiveIncomeTaxRateReconciliationAtFederalStatutoryIncomeTaxRate" order="10850.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="zfgn_IncomeTaxesDisclosureLineItems" xlink:to="zfgn_TaxCutsAndJobsActOf2017NetOperatingLossesCarryforwardMaximumPercentageOfTaxableIncome" order="10890.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="zfgn_IncomeTaxesDisclosureLineItems" xlink:to="zfgn_TaxCutsAndJobsActOf2017IncompleteAccountingChangeInTaxRateDeferredTaxLiabilityProvisionalIncomeTaxBenefit" order="10980.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="zfgn_IncomeTaxesDisclosureLineItems" xlink:to="zfgn_TaxCutsAndJobsActOf2017ChangeInTaxRateIncomeTaxExpenseBenefit" order="11000.00" priority="2" use="optional" />
  </definitionLink>
  <roleRef roleURI="http://www.zafgen.com/20181231/taxonomy/role/DisclosureRetirementPlanAdditionalInformationDetail" xlink:href="zfgn-20181231.xsd#Role_DisclosureRetirementPlanAdditionalInformationDetail" xlink:type="simple" />
  <definitionLink xlink:type="extended" xlink:role="http://www.zafgen.com/20181231/taxonomy/role/DisclosureRetirementPlanAdditionalInformationDetail">
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_DefinedContributionPlanCostRecognized" xlink:type="locator" xlink:label="us-gaap_DefinedContributionPlanCostRecognized" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_DefinedContributionPlanEmployerMatchingContributionPercent" xlink:type="locator" xlink:label="us-gaap_DefinedContributionPlanEmployerMatchingContributionPercent" />
    <loc xlink:href="zfgn-20181231.xsd#zfgn_SIMPLEIRAPlanMember" xlink:type="locator" xlink:label="zfgn_SIMPLEIRAPlanMember" />
    <loc xlink:href="zfgn-20181231.xsd#zfgn_Retirement401KPlanMember" xlink:type="locator" xlink:label="zfgn_Retirement401KPlanMember" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_RetirementPlanTypeDomain" xlink:type="locator" xlink:label="us-gaap_RetirementPlanTypeDomain" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_RetirementPlanTypeDomain" xlink:type="locator" xlink:label="us-gaap_RetirementPlanTypeDomain_2" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_RetirementPlanTypeAxis" xlink:type="locator" xlink:label="us-gaap_RetirementPlanTypeAxis" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_DefinedContributionPlanTable" xlink:type="locator" xlink:label="us-gaap_DefinedContributionPlanTable" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_DefinedContributionPlanDisclosureLineItems" xlink:type="locator" xlink:label="us-gaap_DefinedContributionPlanDisclosureLineItems" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/all" xlink:from="us-gaap_DefinedContributionPlanDisclosureLineItems" xlink:to="us-gaap_DefinedContributionPlanTable" order="10010.00" priority="2" use="optional" xbrldt:contextElement="segment" xbrldt:closed="true" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="us-gaap_DefinedContributionPlanTable" xlink:to="us-gaap_RetirementPlanTypeAxis" order="10040.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="us-gaap_RetirementPlanTypeAxis" xlink:to="us-gaap_RetirementPlanTypeDomain_2" order="10050.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="us-gaap_RetirementPlanTypeAxis" xlink:to="us-gaap_RetirementPlanTypeDomain" order="10070.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_RetirementPlanTypeDomain" xlink:to="zfgn_Retirement401KPlanMember" order="10090.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_RetirementPlanTypeDomain" xlink:to="zfgn_SIMPLEIRAPlanMember" order="10150.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_DefinedContributionPlanDisclosureLineItems" xlink:to="us-gaap_DefinedContributionPlanEmployerMatchingContributionPercent" order="10180.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_DefinedContributionPlanDisclosureLineItems" xlink:to="us-gaap_DefinedContributionPlanCostRecognized" order="10230.00" priority="2" use="optional" />
  </definitionLink>
  <roleRef roleURI="http://www.zafgen.com/20181231/taxonomy/role/DisclosureAustraliaResearchAndDevelopmentTaxIncentiveAdditionalInformationDetail" xlink:href="zfgn-20181231.xsd#Role_DisclosureAustraliaResearchAndDevelopmentTaxIncentiveAdditionalInformationDetail" xlink:type="simple" />
  <definitionLink xlink:type="extended" xlink:role="http://www.zafgen.com/20181231/taxonomy/role/DisclosureAustraliaResearchAndDevelopmentTaxIncentiveAdditionalInformationDetail">
    <loc xlink:href="zfgn-20181231.xsd#zfgn_TaxIncentiveReceivable" xlink:type="locator" xlink:label="zfgn_TaxIncentiveReceivable" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_ForeignCurrencyTransactionGainLossUnrealized" xlink:type="locator" xlink:label="us-gaap_ForeignCurrencyTransactionGainLossUnrealized" />
    <loc xlink:href="zfgn-20181231.xsd#zfgn_PercentageReductionResearchAndDevelopmentCosts" xlink:type="locator" xlink:label="zfgn_PercentageReductionResearchAndDevelopmentCosts" />
    <loc xlink:href="zfgn-20181231.xsd#zfgn_TaxIncentiveResearchAndDevelopmentActivities" xlink:type="locator" xlink:label="zfgn_TaxIncentiveResearchAndDevelopmentActivities" />
    <loc xlink:href="zfgn-20181231.xsd#zfgn_EffectiveTaxIncentiveRateRelatedToResearchAndDevelopment" xlink:type="locator" xlink:label="zfgn_EffectiveTaxIncentiveRateRelatedToResearchAndDevelopment" />
    <loc xlink:href="http://xbrl.sec.gov/country/2017/country-2017-01-31.xsd#country_AU" xlink:type="locator" xlink:label="country_AU" />
    <loc xlink:href="http://xbrl.fasb.org/srt/2018/elts/srt-2018-01-31.xsd#srt_SegmentGeographicalDomain" xlink:type="locator" xlink:label="srt_SegmentGeographicalDomain" />
    <loc xlink:href="http://xbrl.fasb.org/srt/2018/elts/srt-2018-01-31.xsd#srt_SegmentGeographicalDomain" xlink:type="locator" xlink:label="srt_SegmentGeographicalDomain_2" />
    <loc xlink:href="http://xbrl.fasb.org/srt/2018/elts/srt-2018-01-31.xsd#srt_StatementGeographicalAxis" xlink:type="locator" xlink:label="srt_StatementGeographicalAxis" />
    <loc xlink:href="http://xbrl.fasb.org/srt/2018/elts/srt-2018-01-31.xsd#srt_MinimumMember" xlink:type="locator" xlink:label="srt_MinimumMember" />
    <loc xlink:href="http://xbrl.fasb.org/srt/2018/elts/srt-2018-01-31.xsd#srt_MaximumMember" xlink:type="locator" xlink:label="srt_MaximumMember" />
    <loc xlink:href="http://xbrl.fasb.org/srt/2018/elts/srt-2018-01-31.xsd#srt_RangeMember" xlink:type="locator" xlink:label="srt_RangeMember" />
    <loc xlink:href="http://xbrl.fasb.org/srt/2018/elts/srt-2018-01-31.xsd#srt_RangeAxis" xlink:type="locator" xlink:label="srt_RangeAxis" />
    <loc xlink:href="http://xbrl.fasb.org/srt/2018/elts/srt-2018-01-31.xsd#srt_SubsidiariesMember" xlink:type="locator" xlink:label="srt_SubsidiariesMember" />
    <loc xlink:href="http://xbrl.fasb.org/srt/2018/elts/srt-2018-01-31.xsd#srt_ConsolidatedEntitiesDomain" xlink:type="locator" xlink:label="srt_ConsolidatedEntitiesDomain" />
    <loc xlink:href="http://xbrl.fasb.org/srt/2018/elts/srt-2018-01-31.xsd#srt_ConsolidatedEntitiesDomain" xlink:type="locator" xlink:label="srt_ConsolidatedEntitiesDomain_2" />
    <loc xlink:href="http://xbrl.fasb.org/srt/2018/elts/srt-2018-01-31.xsd#srt_ConsolidatedEntitiesAxis" xlink:type="locator" xlink:label="srt_ConsolidatedEntitiesAxis" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_ResearchAndDevelopmentExpenseMember" xlink:type="locator" xlink:label="us-gaap_ResearchAndDevelopmentExpenseMember" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_IncomeStatementLocationDomain" xlink:type="locator" xlink:label="us-gaap_IncomeStatementLocationDomain" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_IncomeStatementLocationAxis" xlink:type="locator" xlink:label="us-gaap_IncomeStatementLocationAxis" />
    <loc xlink:href="zfgn-20181231.xsd#zfgn_ResearchAndDevelopmentExpensesTable" xlink:type="locator" xlink:label="zfgn_ResearchAndDevelopmentExpensesTable" />
    <loc xlink:href="zfgn-20181231.xsd#zfgn_ResearchAndDevelopmentTaxIncentiveLineItems" xlink:type="locator" xlink:label="zfgn_ResearchAndDevelopmentTaxIncentiveLineItems" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/all" xlink:from="zfgn_ResearchAndDevelopmentTaxIncentiveLineItems" xlink:to="zfgn_ResearchAndDevelopmentExpensesTable" order="10010.00" priority="2" use="optional" xbrldt:contextElement="segment" xbrldt:closed="true" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="zfgn_ResearchAndDevelopmentExpensesTable" xlink:to="us-gaap_IncomeStatementLocationAxis" order="10040.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="us-gaap_IncomeStatementLocationAxis" xlink:to="us-gaap_IncomeStatementLocationDomain" order="10070.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_IncomeStatementLocationDomain" xlink:to="us-gaap_ResearchAndDevelopmentExpenseMember" order="10090.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="zfgn_ResearchAndDevelopmentExpensesTable" xlink:to="srt_ConsolidatedEntitiesAxis" order="10140.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="srt_ConsolidatedEntitiesAxis" xlink:to="srt_ConsolidatedEntitiesDomain_2" order="10150.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="srt_ConsolidatedEntitiesAxis" xlink:to="srt_ConsolidatedEntitiesDomain" order="10170.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="srt_ConsolidatedEntitiesDomain" xlink:to="srt_SubsidiariesMember" order="10190.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="zfgn_ResearchAndDevelopmentExpensesTable" xlink:to="srt_RangeAxis" order="10300.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="srt_RangeAxis" xlink:to="srt_RangeMember" order="10330.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="srt_RangeMember" xlink:to="srt_MaximumMember" order="10350.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="srt_RangeMember" xlink:to="srt_MinimumMember" order="10370.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="zfgn_ResearchAndDevelopmentExpensesTable" xlink:to="srt_StatementGeographicalAxis" order="10380.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="srt_StatementGeographicalAxis" xlink:to="srt_SegmentGeographicalDomain_2" order="10390.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="srt_StatementGeographicalAxis" xlink:to="srt_SegmentGeographicalDomain" order="10410.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="srt_SegmentGeographicalDomain" xlink:to="country_AU" order="10430.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="zfgn_ResearchAndDevelopmentTaxIncentiveLineItems" xlink:to="zfgn_EffectiveTaxIncentiveRateRelatedToResearchAndDevelopment" order="10460.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="zfgn_ResearchAndDevelopmentTaxIncentiveLineItems" xlink:to="zfgn_TaxIncentiveResearchAndDevelopmentActivities" order="10520.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="zfgn_ResearchAndDevelopmentTaxIncentiveLineItems" xlink:to="zfgn_PercentageReductionResearchAndDevelopmentCosts" order="10580.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="zfgn_ResearchAndDevelopmentTaxIncentiveLineItems" xlink:to="us-gaap_ForeignCurrencyTransactionGainLossUnrealized" order="10640.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="zfgn_ResearchAndDevelopmentTaxIncentiveLineItems" xlink:to="zfgn_TaxIncentiveReceivable" order="10760.00" priority="2" use="optional" />
  </definitionLink>
  <roleRef roleURI="http://www.zafgen.com/20181231/taxonomy/role/DisclosureRestructuringSummaryOfRestructuringCostsByCategoryDetail" xlink:href="zfgn-20181231.xsd#Role_DisclosureRestructuringSummaryOfRestructuringCostsByCategoryDetail" xlink:type="simple" />
  <definitionLink xlink:type="extended" xlink:role="http://www.zafgen.com/20181231/taxonomy/role/DisclosureRestructuringSummaryOfRestructuringCostsByCategoryDetail">
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_RestructuringCosts" xlink:type="locator" xlink:label="us-gaap_RestructuringCosts" />
    <loc xlink:href="zfgn-20181231.xsd#zfgn_NonCashMember" xlink:type="locator" xlink:label="zfgn_NonCashMember" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_GeneralAndAdministrativeExpenseMember" xlink:type="locator" xlink:label="us-gaap_GeneralAndAdministrativeExpenseMember" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_ResearchAndDevelopmentExpenseMember" xlink:type="locator" xlink:label="us-gaap_ResearchAndDevelopmentExpenseMember" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_IncomeStatementLocationDomain" xlink:type="locator" xlink:label="us-gaap_IncomeStatementLocationDomain" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_IncomeStatementLocationAxis" xlink:type="locator" xlink:label="us-gaap_IncomeStatementLocationAxis" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_CashMember" xlink:type="locator" xlink:label="us-gaap_CashMember" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_RestrictedCashAndCashEquivalentsCashAndCashEquivalentsMember" xlink:type="locator" xlink:label="us-gaap_RestrictedCashAndCashEquivalentsCashAndCashEquivalentsMember" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_RestrictedCashAndCashEquivalentsCashAndCashEquivalentsMember" xlink:type="locator" xlink:label="us-gaap_RestrictedCashAndCashEquivalentsCashAndCashEquivalentsMember_2" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_CashAndCashEquivalentsAxis" xlink:type="locator" xlink:label="us-gaap_CashAndCashEquivalentsAxis" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_ScheduleOfRestructuringAndRelatedCostsTable" xlink:type="locator" xlink:label="us-gaap_ScheduleOfRestructuringAndRelatedCostsTable" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_RestructuringReserveLineItems" xlink:type="locator" xlink:label="us-gaap_RestructuringReserveLineItems" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/all" xlink:from="us-gaap_RestructuringReserveLineItems" xlink:to="us-gaap_ScheduleOfRestructuringAndRelatedCostsTable" order="10010.00" priority="2" use="optional" xbrldt:contextElement="segment" xbrldt:closed="true" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="us-gaap_ScheduleOfRestructuringAndRelatedCostsTable" xlink:to="us-gaap_CashAndCashEquivalentsAxis" order="10040.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="us-gaap_CashAndCashEquivalentsAxis" xlink:to="us-gaap_RestrictedCashAndCashEquivalentsCashAndCashEquivalentsMember_2" order="10050.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="us-gaap_CashAndCashEquivalentsAxis" xlink:to="us-gaap_RestrictedCashAndCashEquivalentsCashAndCashEquivalentsMember" order="10070.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_RestrictedCashAndCashEquivalentsCashAndCashEquivalentsMember" xlink:to="us-gaap_CashMember" order="10090.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="us-gaap_ScheduleOfRestructuringAndRelatedCostsTable" xlink:to="us-gaap_IncomeStatementLocationAxis" order="10140.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="us-gaap_IncomeStatementLocationAxis" xlink:to="us-gaap_IncomeStatementLocationDomain" order="10170.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_IncomeStatementLocationDomain" xlink:to="us-gaap_ResearchAndDevelopmentExpenseMember" order="10190.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_IncomeStatementLocationDomain" xlink:to="us-gaap_GeneralAndAdministrativeExpenseMember" order="10210.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_RestrictedCashAndCashEquivalentsCashAndCashEquivalentsMember" xlink:to="zfgn_NonCashMember" order="10270.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_RestructuringReserveLineItems" xlink:to="us-gaap_RestructuringCosts" order="10500.00" priority="2" use="optional" />
  </definitionLink>
  <roleRef roleURI="http://www.zafgen.com/20181231/taxonomy/role/DisclosureSubsequentEventsAdditionalInformationDetail" xlink:href="zfgn-20181231.xsd#Role_DisclosureSubsequentEventsAdditionalInformationDetail" xlink:type="simple" />
  <definitionLink xlink:type="extended" xlink:role="http://www.zafgen.com/20181231/taxonomy/role/DisclosureSubsequentEventsAdditionalInformationDetail">
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_LineOfCredit" xlink:type="locator" xlink:label="us-gaap_LineOfCredit" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_LesseeOperatingLeaseRenewalTerm" xlink:type="locator" xlink:label="us-gaap_LesseeOperatingLeaseRenewalTerm" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_LesseeOperatingLeaseTermOfContract" xlink:type="locator" xlink:label="us-gaap_LesseeOperatingLeaseTermOfContract" />
    <loc xlink:href="zfgn-20181231.xsd#zfgn_AreaOfOfficeSpace" xlink:type="locator" xlink:label="zfgn_AreaOfOfficeSpace" />
    <loc xlink:href="zfgn-20181231.xsd#zfgn_OperatingLeaseCommencementDate" xlink:type="locator" xlink:label="zfgn_OperatingLeaseCommencementDate" />
    <loc xlink:href="zfgn-20181231.xsd#zfgn_ShigoCenterPlazaOwnersLLCMember" xlink:type="locator" xlink:label="zfgn_ShigoCenterPlazaOwnersLLCMember" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_LeaseArrangementTypeDomain" xlink:type="locator" xlink:label="us-gaap_LeaseArrangementTypeDomain" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_LeaseArrangementTypeAxis" xlink:type="locator" xlink:label="us-gaap_LeaseArrangementTypeAxis" />
    <loc xlink:href="https://xbrl.sec.gov/stpr/2018/stpr-2018-01-31.xsd#stpr_MA" xlink:type="locator" xlink:label="stpr_MA" />
    <loc xlink:href="http://xbrl.fasb.org/srt/2018/elts/srt-2018-01-31.xsd#srt_SegmentGeographicalDomain" xlink:type="locator" xlink:label="srt_SegmentGeographicalDomain" />
    <loc xlink:href="http://xbrl.fasb.org/srt/2018/elts/srt-2018-01-31.xsd#srt_StatementGeographicalAxis" xlink:type="locator" xlink:label="srt_StatementGeographicalAxis" />
    <loc xlink:href="zfgn-20181231.xsd#zfgn_BostonMember" xlink:type="locator" xlink:label="zfgn_BostonMember" />
    <loc xlink:href="https://xbrl.sec.gov/dei/2018/dei-2018-01-31.xsd#dei_LocationDomain" xlink:type="locator" xlink:label="dei_LocationDomain" />
    <loc xlink:href="https://xbrl.sec.gov/dei/2018/dei-2018-01-31.xsd#dei_LocationDomain" xlink:type="locator" xlink:label="dei_LocationDomain_2" />
    <loc xlink:href="https://xbrl.sec.gov/dei/2018/dei-2018-01-31.xsd#dei_EntityByLocationAxis" xlink:type="locator" xlink:label="dei_EntityByLocationAxis" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_SubsequentEventMember" xlink:type="locator" xlink:label="us-gaap_SubsequentEventMember" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_SubsequentEventTypeDomain" xlink:type="locator" xlink:label="us-gaap_SubsequentEventTypeDomain" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_SubsequentEventTypeDomain" xlink:type="locator" xlink:label="us-gaap_SubsequentEventTypeDomain_2" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_SubsequentEventTypeAxis" xlink:type="locator" xlink:label="us-gaap_SubsequentEventTypeAxis" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_SubsequentEventTable" xlink:type="locator" xlink:label="us-gaap_SubsequentEventTable" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_SubsequentEventLineItems" xlink:type="locator" xlink:label="us-gaap_SubsequentEventLineItems" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/all" xlink:from="us-gaap_SubsequentEventLineItems" xlink:to="us-gaap_SubsequentEventTable" order="10010.00" priority="2" use="optional" xbrldt:contextElement="segment" xbrldt:closed="true" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="us-gaap_SubsequentEventTable" xlink:to="us-gaap_SubsequentEventTypeAxis" order="10040.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="us-gaap_SubsequentEventTypeAxis" xlink:to="us-gaap_SubsequentEventTypeDomain_2" order="10050.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="us-gaap_SubsequentEventTypeAxis" xlink:to="us-gaap_SubsequentEventTypeDomain" order="10070.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_SubsequentEventTypeDomain" xlink:to="us-gaap_SubsequentEventMember" order="10090.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="us-gaap_SubsequentEventTable" xlink:to="dei_EntityByLocationAxis" order="10100.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="dei_EntityByLocationAxis" xlink:to="dei_LocationDomain_2" order="10110.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="dei_EntityByLocationAxis" xlink:to="dei_LocationDomain" order="10130.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="dei_LocationDomain" xlink:to="zfgn_BostonMember" order="10150.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="us-gaap_SubsequentEventTable" xlink:to="srt_StatementGeographicalAxis" order="10240.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="srt_StatementGeographicalAxis" xlink:to="srt_SegmentGeographicalDomain" order="10270.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="srt_SegmentGeographicalDomain" xlink:to="stpr_MA" order="10290.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="us-gaap_SubsequentEventTable" xlink:to="us-gaap_LeaseArrangementTypeAxis" order="10380.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="us-gaap_LeaseArrangementTypeAxis" xlink:to="us-gaap_LeaseArrangementTypeDomain" order="10410.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_LeaseArrangementTypeDomain" xlink:to="zfgn_ShigoCenterPlazaOwnersLLCMember" order="10430.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_SubsequentEventLineItems" xlink:to="zfgn_OperatingLeaseCommencementDate" order="10540.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_SubsequentEventLineItems" xlink:to="zfgn_AreaOfOfficeSpace" order="10560.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_SubsequentEventLineItems" xlink:to="us-gaap_LesseeOperatingLeaseTermOfContract" order="10580.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_SubsequentEventLineItems" xlink:to="us-gaap_LesseeOperatingLeaseRenewalTerm" order="10600.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_SubsequentEventLineItems" xlink:to="us-gaap_LineOfCredit" order="10620.00" priority="2" use="optional" />
  </definitionLink>
  <roleRef roleURI="http://www.zafgen.com/20181231/taxonomy/role/DisclosureSubsequentEventsScheduleOfMonthlyBaseRentDetail" xlink:href="zfgn-20181231.xsd#Role_DisclosureSubsequentEventsScheduleOfMonthlyBaseRentDetail" xlink:type="simple" />
  <definitionLink xlink:type="extended" xlink:role="http://www.zafgen.com/20181231/taxonomy/role/DisclosureSubsequentEventsScheduleOfMonthlyBaseRentDetail">
    <loc xlink:href="zfgn-20181231.xsd#zfgn_OperatingLeasesRentExpenseMonthlyBaseRentDueInYearTen" xlink:type="locator" xlink:label="zfgn_OperatingLeasesRentExpenseMonthlyBaseRentDueInYearTen" />
    <loc xlink:href="zfgn-20181231.xsd#zfgn_OperatingLeasesRentExpenseMonthlyBaseRentDueInYearNine" xlink:type="locator" xlink:label="zfgn_OperatingLeasesRentExpenseMonthlyBaseRentDueInYearNine" />
    <loc xlink:href="zfgn-20181231.xsd#zfgn_OperatingLeasesRentExpenseMonthlyBaseRentDueInYearEight" xlink:type="locator" xlink:label="zfgn_OperatingLeasesRentExpenseMonthlyBaseRentDueInYearEight" />
    <loc xlink:href="zfgn-20181231.xsd#zfgn_OperatingLeasesRentExpenseMonthlyBaseRentDueInYearSeven" xlink:type="locator" xlink:label="zfgn_OperatingLeasesRentExpenseMonthlyBaseRentDueInYearSeven" />
    <loc xlink:href="zfgn-20181231.xsd#zfgn_OperatingLeasesRentExpenseMonthlyBaseRentDueInYearSix" xlink:type="locator" xlink:label="zfgn_OperatingLeasesRentExpenseMonthlyBaseRentDueInYearSix" />
    <loc xlink:href="zfgn-20181231.xsd#zfgn_OperatingLeasesRentExpenseMonthlyBaseRentDueInYearFive" xlink:type="locator" xlink:label="zfgn_OperatingLeasesRentExpenseMonthlyBaseRentDueInYearFive" />
    <loc xlink:href="zfgn-20181231.xsd#zfgn_OperatingLeasesRentExpenseMonthlyBaseRentDueInYearFour" xlink:type="locator" xlink:label="zfgn_OperatingLeasesRentExpenseMonthlyBaseRentDueInYearFour" />
    <loc xlink:href="zfgn-20181231.xsd#zfgn_OperatingLeasesRentExpenseMonthlyBaseRentDueInYearThree" xlink:type="locator" xlink:label="zfgn_OperatingLeasesRentExpenseMonthlyBaseRentDueInYearThree" />
    <loc xlink:href="zfgn-20181231.xsd#zfgn_OperatingLeasesRentExpenseMonthlyBaseRentDueInYearTwo" xlink:type="locator" xlink:label="zfgn_OperatingLeasesRentExpenseMonthlyBaseRentDueInYearTwo" />
    <loc xlink:href="zfgn-20181231.xsd#zfgn_OperatingLeasesRentExpenseMonthlyBaseRentDueInYearOne" xlink:type="locator" xlink:label="zfgn_OperatingLeasesRentExpenseMonthlyBaseRentDueInYearOne" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_SubsequentEventMember" xlink:type="locator" xlink:label="us-gaap_SubsequentEventMember" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_SubsequentEventTypeDomain" xlink:type="locator" xlink:label="us-gaap_SubsequentEventTypeDomain" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_SubsequentEventTypeAxis" xlink:type="locator" xlink:label="us-gaap_SubsequentEventTypeAxis" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_SubsequentEventTable" xlink:type="locator" xlink:label="us-gaap_SubsequentEventTable" />
    <loc xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_SubsequentEventLineItems" xlink:type="locator" xlink:label="us-gaap_SubsequentEventLineItems" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/all" xlink:from="us-gaap_SubsequentEventLineItems" xlink:to="us-gaap_SubsequentEventTable" order="10010.00" priority="2" use="optional" xbrldt:contextElement="segment" xbrldt:closed="true" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="us-gaap_SubsequentEventTable" xlink:to="us-gaap_SubsequentEventTypeAxis" order="10040.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="us-gaap_SubsequentEventTypeAxis" xlink:to="us-gaap_SubsequentEventTypeDomain" order="10070.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_SubsequentEventTypeDomain" xlink:to="us-gaap_SubsequentEventMember" order="10090.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_SubsequentEventLineItems" xlink:to="zfgn_OperatingLeasesRentExpenseMonthlyBaseRentDueInYearOne" order="10120.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_SubsequentEventLineItems" xlink:to="zfgn_OperatingLeasesRentExpenseMonthlyBaseRentDueInYearTwo" order="10140.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_SubsequentEventLineItems" xlink:to="zfgn_OperatingLeasesRentExpenseMonthlyBaseRentDueInYearThree" order="10160.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_SubsequentEventLineItems" xlink:to="zfgn_OperatingLeasesRentExpenseMonthlyBaseRentDueInYearFour" order="10180.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_SubsequentEventLineItems" xlink:to="zfgn_OperatingLeasesRentExpenseMonthlyBaseRentDueInYearFive" order="10200.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_SubsequentEventLineItems" xlink:to="zfgn_OperatingLeasesRentExpenseMonthlyBaseRentDueInYearSix" order="10220.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_SubsequentEventLineItems" xlink:to="zfgn_OperatingLeasesRentExpenseMonthlyBaseRentDueInYearSeven" order="10240.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_SubsequentEventLineItems" xlink:to="zfgn_OperatingLeasesRentExpenseMonthlyBaseRentDueInYearEight" order="10260.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_SubsequentEventLineItems" xlink:to="zfgn_OperatingLeasesRentExpenseMonthlyBaseRentDueInYearNine" order="10280.00" priority="2" use="optional" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_SubsequentEventLineItems" xlink:to="zfgn_OperatingLeasesRentExpenseMonthlyBaseRentDueInYearTen" order="10300.00" priority="2" use="optional" />
  </definitionLink>
</linkbase>
