<?xml version="1.0" encoding="us-ascii"?>
<!-- DFIN ActiveDisclosure(SM) XBRL Schema Document - http://www.dfinsolutions.com/ -->
<!-- Creation Date      : 2019-05-09T15:38:36.0744032+00:00 -->
<!-- Version            : 3.4.7044.22220 -->
<!-- Package ID         : c0e94e40bc874d84b32b595aab181f8a -->
<!-- Copyright (c) 2019 Donnelley Financial Solutions, Inc. All Rights Reserved. -->
<xsd:schema xmlns:nonnum="http://www.xbrl.org/dtr/type/non-numeric" xmlns:num="http://www.xbrl.org/dtr/type/numeric" xmlns:us-types="http://fasb.org/us-types/2018-01-31" xmlns:stpr="http://xbrl.sec.gov/stpr/2018-01-31" xmlns:srt-types="http://fasb.org/srt-types/2018-01-31" xmlns:zfgn="http://www.zafgen.com/20190331" xmlns:naics="http://xbrl.sec.gov/naics/2017-01-31" xmlns:invest="http://xbrl.sec.gov/invest/2013-01-31" xmlns:xbrldt="http://xbrl.org/2005/xbrldt" xmlns:srt="http://fasb.org/srt/2018-01-31" xmlns:us-gaap="http://fasb.org/us-gaap/2018-01-31" xmlns:dei="http://xbrl.sec.gov/dei/2018-01-31" xmlns:xbrli="http://www.xbrl.org/2003/instance" xmlns:country="http://xbrl.sec.gov/country/2017-01-31" xmlns:link="http://www.xbrl.org/2003/linkbase" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:currency="http://xbrl.sec.gov/currency/2017-01-31" xmlns:exch="http://xbrl.sec.gov/exch/2018-01-31" xmlns:sic="http://xbrl.sec.gov/sic/2011-01-31" attributeFormDefault="unqualified" elementFormDefault="qualified" targetNamespace="http://www.zafgen.com/20190331" xmlns:xsd="http://www.w3.org/2001/XMLSchema">
  <xsd:import schemaLocation="http://www.xbrl.org/2003/xbrl-instance-2003-12-31.xsd" namespace="http://www.xbrl.org/2003/instance" />
  <xsd:import schemaLocation="http://www.xbrl.org/2003/xbrl-linkbase-2003-12-31.xsd" namespace="http://www.xbrl.org/2003/linkbase" />
  <xsd:import schemaLocation="http://www.xbrl.org/2005/xbrldt-2005.xsd" namespace="http://xbrl.org/2005/xbrldt" />
  <xsd:import schemaLocation="https://xbrl.sec.gov/dei/2018/dei-2018-01-31.xsd" namespace="http://xbrl.sec.gov/dei/2018-01-31" />
  <xsd:import schemaLocation="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd" namespace="http://fasb.org/us-gaap/2018-01-31" />
  <xsd:import schemaLocation="http://xbrl.fasb.org/srt/2018/elts/srt-2018-01-31.xsd" namespace="http://fasb.org/srt/2018-01-31" />
  <xsd:import schemaLocation="http://xbrl.fasb.org/us-gaap/2018/elts/us-types-2018-01-31.xsd" namespace="http://fasb.org/us-types/2018-01-31" />
  <xsd:import schemaLocation="http://www.xbrl.org/dtr/type/numeric-2009-12-16.xsd" namespace="http://www.xbrl.org/dtr/type/numeric" />
  <xsd:import schemaLocation="http://www.xbrl.org/dtr/type/nonNumeric-2009-12-16.xsd" namespace="http://www.xbrl.org/dtr/type/non-numeric" />
  <xsd:import schemaLocation="http://xbrl.fasb.org/srt/2018/elts/srt-types-2018-01-31.xsd" namespace="http://fasb.org/srt-types/2018-01-31" />
  <xsd:import schemaLocation="http://xbrl.sec.gov/country/2017/country-2017-01-31.xsd" namespace="http://xbrl.sec.gov/country/2017-01-31" />
  <xsd:import schemaLocation="https://xbrl.sec.gov/currency/2017/currency-2017-01-31.xsd" namespace="http://xbrl.sec.gov/currency/2017-01-31" />
  <xsd:import schemaLocation="https://xbrl.sec.gov/exch/2018/exch-2018-01-31.xsd" namespace="http://xbrl.sec.gov/exch/2018-01-31" />
  <xsd:import schemaLocation="https://xbrl.sec.gov/invest/2013/invest-2013-01-31.xsd" namespace="http://xbrl.sec.gov/invest/2013-01-31" />
  <xsd:import schemaLocation="https://xbrl.sec.gov/naics/2017/naics-2017-01-31.xsd" namespace="http://xbrl.sec.gov/naics/2017-01-31" />
  <xsd:import schemaLocation="https://xbrl.sec.gov/sic/2011/sic-2011-01-31.xsd" namespace="http://xbrl.sec.gov/sic/2011-01-31" />
  <xsd:import schemaLocation="https://xbrl.sec.gov/stpr/2018/stpr-2018-01-31.xsd" namespace="http://xbrl.sec.gov/stpr/2018-01-31" />
  <xsd:annotation>
    <xsd:appinfo>
      <link:roleType id="TemplateLink" roleURI="http://www.zafgen.com/20190331/role/TemplateLink" xmlns:link="http://www.xbrl.org/2003/linkbase">
        <link:definition>00000 - Document - Template Link</link:definition>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:linkbaseRef xlink:arcrole="http://www.w3.org/1999/xlink/properties/linkbase" xlink:href="zfgn-20190331_cal.xml" xlink:role="http://www.xbrl.org/2003/role/calculationLinkbaseRef" xlink:title="Calculation Links, all" xlink:type="simple" xmlns:link="http://www.xbrl.org/2003/linkbase" xmlns:xlink="http://www.w3.org/1999/xlink" />
      <link:linkbaseRef xlink:arcrole="http://www.w3.org/1999/xlink/properties/linkbase" xlink:href="zfgn-20190331_def.xml" xlink:role="http://www.xbrl.org/2003/role/definitionLinkbaseRef" xlink:title="Definition Links, all" xlink:type="simple" />
      <link:linkbaseRef xlink:arcrole="http://www.w3.org/1999/xlink/properties/linkbase" xlink:href="zfgn-20190331_lab.xml" xlink:role="http://www.xbrl.org/2003/role/labelLinkbaseRef" xlink:title="Label Links, all" xlink:type="simple" />
      <link:linkbaseRef xlink:arcrole="http://www.w3.org/1999/xlink/properties/linkbase" xlink:href="zfgn-20190331_pre.xml" xlink:role="http://www.xbrl.org/2003/role/presentationLinkbaseRef" xlink:title="Presentation Links, all" xlink:type="simple" />
      <link:roleType roleURI="http://www.zafgen.com/20190331/taxonomy/role/DocumentDocumentAndEntityInformation" id="Role_DocumentDocumentAndEntityInformation">
        <link:definition>100000 - Document - Document and Entity Information</link:definition>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType roleURI="http://www.zafgen.com/20190331/taxonomy/role/StatementCondensedConsolidatedBalanceSheets" id="Role_StatementCondensedConsolidatedBalanceSheets">
        <link:definition>100010 - Statement - Condensed Consolidated Balance Sheets</link:definition>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType roleURI="http://www.zafgen.com/20190331/taxonomy/role/StatementCondensedConsolidatedBalanceSheetsParenthetical" id="Role_StatementCondensedConsolidatedBalanceSheetsParenthetical">
        <link:definition>100020 - Statement - Condensed Consolidated Balance Sheets (Parenthetical)</link:definition>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType roleURI="http://www.zafgen.com/20190331/taxonomy/role/StatementCondensedConsolidatedStatementsOfOperationsAndComprehensiveLoss" id="Role_StatementCondensedConsolidatedStatementsOfOperationsAndComprehensiveLoss">
        <link:definition>100030 - Statement - Condensed Consolidated Statements of Operations and Comprehensive Loss</link:definition>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType roleURI="http://www.zafgen.com/20190331/taxonomy/role/StatementCondensedConsolidatedStatementsOfChangesInStockholdersEquity" id="Role_StatementCondensedConsolidatedStatementsOfChangesInStockholdersEquity">
        <link:definition>100040 - Statement - Condensed Consolidated Statements of Changes in Stockholders&apos; Equity</link:definition>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType roleURI="http://www.zafgen.com/20190331/taxonomy/role/StatementCondensedConsolidatedStatementsOfCashFlows" id="Role_StatementCondensedConsolidatedStatementsOfCashFlows">
        <link:definition>100050 - Statement - Condensed Consolidated Statements of Cash Flows</link:definition>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType roleURI="http://www.zafgen.com/20190331/taxonomy/role/DisclosureNatureOfBusinessAndBasisOfPresentation" id="Role_DisclosureNatureOfBusinessAndBasisOfPresentation">
        <link:definition>100060 - Disclosure - Nature of the Business and Basis of Presentation</link:definition>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType roleURI="http://www.zafgen.com/20190331/taxonomy/role/DisclosureSummaryOfSignificantAccountingPolicies" id="Role_DisclosureSummaryOfSignificantAccountingPolicies">
        <link:definition>100070 - Disclosure - Summary of Significant Accounting Policies</link:definition>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType roleURI="http://www.zafgen.com/20190331/taxonomy/role/DisclosureFairValueMeasurementsAndMarketableSecurities" id="Role_DisclosureFairValueMeasurementsAndMarketableSecurities">
        <link:definition>100080 - Disclosure - Fair Value Measurements and Marketable Securities</link:definition>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType roleURI="http://www.zafgen.com/20190331/taxonomy/role/DisclosureAccruedExpensesAndOther" id="Role_DisclosureAccruedExpensesAndOther">
        <link:definition>100090 - Disclosure - Accrued Expenses and Other</link:definition>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType roleURI="http://www.zafgen.com/20190331/taxonomy/role/DisclosureNotesPayable" id="Role_DisclosureNotesPayable">
        <link:definition>100100 - Disclosure - Notes Payable</link:definition>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType roleURI="http://www.zafgen.com/20190331/taxonomy/role/DisclosureStockBasedAwards" id="Role_DisclosureStockBasedAwards">
        <link:definition>100110 - Disclosure - Stock-Based Awards</link:definition>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType roleURI="http://www.zafgen.com/20190331/taxonomy/role/DisclosureCommitmentsAndContingencies" id="Role_DisclosureCommitmentsAndContingencies">
        <link:definition>100120 - Disclosure - Commitments and Contingencies</link:definition>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType roleURI="http://www.zafgen.com/20190331/taxonomy/role/DisclosureRetirementPlan" id="Role_DisclosureRetirementPlan">
        <link:definition>100130 - Disclosure - Retirement Plan</link:definition>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType roleURI="http://www.zafgen.com/20190331/taxonomy/role/DisclosureAustraliaResearchAndDevelopmentTaxIncentive" id="Role_DisclosureAustraliaResearchAndDevelopmentTaxIncentive">
        <link:definition>100140 - Disclosure - Australia Research and Development Tax Incentive</link:definition>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType roleURI="http://www.zafgen.com/20190331/taxonomy/role/DisclosureSummaryOfSignificantAccountingPoliciesPolicies" id="Role_DisclosureSummaryOfSignificantAccountingPoliciesPolicies">
        <link:definition>100150 - Disclosure - Summary of Significant Accounting Policies (Policies)</link:definition>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType roleURI="http://www.zafgen.com/20190331/taxonomy/role/DisclosureSummaryOfSignificantAccountingPoliciesTables" id="Role_DisclosureSummaryOfSignificantAccountingPoliciesTables">
        <link:definition>100160 - Disclosure - Summary of Significant Accounting Policies (Tables)</link:definition>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType roleURI="http://www.zafgen.com/20190331/taxonomy/role/DisclosureFairValueMeasurementsAndMarketableSecuritiesTables" id="Role_DisclosureFairValueMeasurementsAndMarketableSecuritiesTables">
        <link:definition>100170 - Disclosure - Fair Value Measurements and Marketable Securities (Tables)</link:definition>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType roleURI="http://www.zafgen.com/20190331/taxonomy/role/DisclosureAccruedExpensesAndOtherTables" id="Role_DisclosureAccruedExpensesAndOtherTables">
        <link:definition>100180 - Disclosure - Accrued Expenses and Other (Tables)</link:definition>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType roleURI="http://www.zafgen.com/20190331/taxonomy/role/DisclosureNotesPayableTables" id="Role_DisclosureNotesPayableTables">
        <link:definition>100190 - Disclosure - Notes Payable (Tables)</link:definition>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType roleURI="http://www.zafgen.com/20190331/taxonomy/role/DisclosureStockBasedAwardsTables" id="Role_DisclosureStockBasedAwardsTables">
        <link:definition>100200 - Disclosure - Stock-Based Awards (Tables)</link:definition>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType roleURI="http://www.zafgen.com/20190331/taxonomy/role/DisclosureCommitmentsAndContingenciesTables" id="Role_DisclosureCommitmentsAndContingenciesTables">
        <link:definition>100210 - Disclosure - Commitments and Contingencies (Tables)</link:definition>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType roleURI="http://www.zafgen.com/20190331/taxonomy/role/DisclosureNatureOfBusinessAndBasisOfPresentationAdditionalInformationDetail" id="Role_DisclosureNatureOfBusinessAndBasisOfPresentationAdditionalInformationDetail">
        <link:definition>100220 - Disclosure - Nature of the Business and Basis of Presentation - Additional Information (Detail)</link:definition>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType roleURI="http://www.zafgen.com/20190331/taxonomy/role/DisclosureSummaryOfSignificantAccountingPoliciesSummaryOfCommonStockEquivalentsOutstandingDetail" id="Role_DisclosureSummaryOfSignificantAccountingPoliciesSummaryOfCommonStockEquivalentsOutstandingDetail">
        <link:definition>100230 - Disclosure - Summary of Significant Accounting Policies - Summary of Common Stock Equivalents Outstanding (Detail)</link:definition>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType roleURI="http://www.zafgen.com/20190331/taxonomy/role/DisclosureSummaryOfSignificantAccountingPoliciesAdditionalInformationDetail" id="Role_DisclosureSummaryOfSignificantAccountingPoliciesAdditionalInformationDetail">
        <link:definition>100240 - Disclosure - Summary of Significant Accounting Policies - Additional Information (Detail)</link:definition>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType roleURI="http://www.zafgen.com/20190331/taxonomy/role/DisclosureFairValueMeasurementsAndMarketableSecuritiesSummaryOfCashEquivalentsAndMarketableSecuritiesDetail" id="Role_DisclosureFairValueMeasurementsAndMarketableSecuritiesSummaryOfCashEquivalentsAndMarketableSecuritiesDetail">
        <link:definition>100250 - Disclosure - Fair Value Measurements and Marketable Securities - Summary of Cash Equivalents and Marketable Securities (Detail)</link:definition>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType roleURI="http://www.zafgen.com/20190331/taxonomy/role/DisclosureFairValueMeasurementsAndMarketableSecuritiesSummaryOfMarketableSecuritiesDetail" id="Role_DisclosureFairValueMeasurementsAndMarketableSecuritiesSummaryOfMarketableSecuritiesDetail">
        <link:definition>100260 - Disclosure - Fair Value Measurements and Marketable Securities - Summary of Marketable Securities (Detail)</link:definition>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType roleURI="http://www.zafgen.com/20190331/taxonomy/role/DisclosureAccruedExpensesAndOtherScheduleOfAccruedExpensesAndOtherDetail" id="Role_DisclosureAccruedExpensesAndOtherScheduleOfAccruedExpensesAndOtherDetail">
        <link:definition>100270 - Disclosure - Accrued Expenses and Other - Schedule of Accrued Expenses and Other (Detail)</link:definition>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType roleURI="http://www.zafgen.com/20190331/taxonomy/role/DisclosureNotesPayableAdditionalInformationDetail" id="Role_DisclosureNotesPayableAdditionalInformationDetail">
        <link:definition>100280 - Disclosure - Notes Payable - Additional Information (Detail)</link:definition>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType roleURI="http://www.zafgen.com/20190331/taxonomy/role/DisclosureNotesPayableScheduleOfNotesPayableDetail" id="Role_DisclosureNotesPayableScheduleOfNotesPayableDetail">
        <link:definition>100290 - Disclosure - Notes Payable - Schedule of Notes Payable (Detail)</link:definition>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType roleURI="http://www.zafgen.com/20190331/taxonomy/role/DisclosureNotesPayableScheduleOfEstimatedFuturePrincipalPaymentsDetail" id="Role_DisclosureNotesPayableScheduleOfEstimatedFuturePrincipalPaymentsDetail">
        <link:definition>100300 - Disclosure - Notes Payable - Schedule of Estimated Future Principal Payments (Detail)</link:definition>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType roleURI="http://www.zafgen.com/20190331/taxonomy/role/DisclosureStockBasedAwardsAdditionalInformationDetail" id="Role_DisclosureStockBasedAwardsAdditionalInformationDetail">
        <link:definition>100310 - Disclosure - Stock-Based Awards - Additional Information (Detail)</link:definition>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType roleURI="http://www.zafgen.com/20190331/taxonomy/role/DisclosureStockBasedAwardsSummaryOfStockBasedCompensationExpenseRelatedToStockOptionsRestrictedCommonStockAndESPPDetail" id="Role_DisclosureStockBasedAwardsSummaryOfStockBasedCompensationExpenseRelatedToStockOptionsRestrictedCommonStockAndESPPDetail">
        <link:definition>100320 - Disclosure - Stock-Based Awards - Summary of Stock-Based Compensation Expense Related to Stock Options, Restricted Common Stock and ESPP (Detail)</link:definition>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType roleURI="http://www.zafgen.com/20190331/taxonomy/role/DisclosureCommitmentsAndContingenciesAdditionalInformationDetail" id="Role_DisclosureCommitmentsAndContingenciesAdditionalInformationDetail">
        <link:definition>100330 - Disclosure - Commitments and Contingencies - Additional Information (Detail)</link:definition>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType roleURI="http://www.zafgen.com/20190331/taxonomy/role/DisclosureCommitmentsAndContingenciesScheduleOfFutureMinimumLeasePaymentsForOperatingLeasesDetail" id="Role_DisclosureCommitmentsAndContingenciesScheduleOfFutureMinimumLeasePaymentsForOperatingLeasesDetail">
        <link:definition>100340 - Disclosure - Commitments and Contingencies - Schedule of Future Minimum Lease Payments for Operating Leases (Detail)</link:definition>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType roleURI="http://www.zafgen.com/20190331/taxonomy/role/DisclosureCommitmentsAndContingenciesScheduleOfFutureMinimumLeasePaymentsForOperatingLeasesDetail2" id="Role_DisclosureCommitmentsAndContingenciesScheduleOfFutureMinimumLeasePaymentsForOperatingLeasesDetail2">
        <link:definition>100350 - Disclosure - Commitments and Contingencies - Schedule of Future Minimum Lease Payments for Operating Leases (Detail)2</link:definition>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType roleURI="http://www.zafgen.com/20190331/taxonomy/role/DisclosureCommitmentsAndContingenciesScheduleOfFutureMinimumRentalCommitmentsUnderPriorLeaseGuidanceDetail" id="Role_DisclosureCommitmentsAndContingenciesScheduleOfFutureMinimumRentalCommitmentsUnderPriorLeaseGuidanceDetail">
        <link:definition>100360 - Disclosure - Commitments and Contingencies - Schedule of Future Minimum Rental Commitments under Prior Lease Guidance (Detail)</link:definition>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType roleURI="http://www.zafgen.com/20190331/taxonomy/role/DisclosureCommitmentsAndContingenciesScheduleOfComponentsOfLeasesExpenseDetail" id="Role_DisclosureCommitmentsAndContingenciesScheduleOfComponentsOfLeasesExpenseDetail">
        <link:definition>100370 - Disclosure - Commitments and Contingencies - Schedule of Components of Leases Expense (Detail)</link:definition>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType roleURI="http://www.zafgen.com/20190331/taxonomy/role/DisclosureCommitmentsAndContingenciesSummaryOfBalanceSheetInformationRelatedToLeasesDetail" id="Role_DisclosureCommitmentsAndContingenciesSummaryOfBalanceSheetInformationRelatedToLeasesDetail">
        <link:definition>100380 - Disclosure - Commitments and Contingencies - Summary of Balance Sheet Information Related to Leases (Detail)</link:definition>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType roleURI="http://www.zafgen.com/20190331/taxonomy/role/DisclosureCommitmentsAndContingenciesScheduleOfWeightedAverageRemainingLeaseTermAndWeightedAverageDiscountRateOfOperatingLeasesDetail" id="Role_DisclosureCommitmentsAndContingenciesScheduleOfWeightedAverageRemainingLeaseTermAndWeightedAverageDiscountRateOfOperatingLeasesDetail">
        <link:definition>100390 - Disclosure - Commitments and Contingencies - Schedule of Weighted Average Remaining Lease Term and Weighted Average Discount Rate of Operating Leases (Detail)</link:definition>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType roleURI="http://www.zafgen.com/20190331/taxonomy/role/DisclosureRetirementPlanAdditionalInformationDetail" id="Role_DisclosureRetirementPlanAdditionalInformationDetail">
        <link:definition>100400 - Disclosure - Retirement Plan - Additional Information (Detail)</link:definition>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType roleURI="http://www.zafgen.com/20190331/taxonomy/role/DisclosureAustraliaResearchAndDevelopmentTaxIncentiveAdditionalInformationDetail" id="Role_DisclosureAustraliaResearchAndDevelopmentTaxIncentiveAdditionalInformationDetail">
        <link:definition>100410 - Disclosure - Australia Research and Development Tax Incentive - Additional Information (Detail)</link:definition>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
    </xsd:appinfo>
  </xsd:annotation>
  <xsd:element id="zfgn_DocumentAndEntityInformationAbstract" name="DocumentAndEntityInformationAbstract" type="xbrli:stringItemType" substitutionGroup="xbrli:item" xbrli:periodType="duration" nillable="true" abstract="true" />
  <xsd:element id="zfgn_TaxIncentiveReceivableCurrent" name="TaxIncentiveReceivableCurrent" type="xbrli:monetaryItemType" substitutionGroup="xbrli:item" xbrli:periodType="instant" nillable="true" abstract="false" xbrli:balance="debit" />
  <xsd:element id="zfgn_TaxIncentiveReceivableNoncurrent" name="TaxIncentiveReceivableNoncurrent" type="xbrli:monetaryItemType" substitutionGroup="xbrli:item" xbrli:periodType="instant" nillable="true" abstract="false" xbrli:balance="debit" />
  <xsd:element id="zfgn_StockIssuedDuringPeriodSharesStockOptionsExercisedAndEmployeeStockPurchasePlans" name="StockIssuedDuringPeriodSharesStockOptionsExercisedAndEmployeeStockPurchasePlans" type="xbrli:sharesItemType" substitutionGroup="xbrli:item" xbrli:periodType="duration" nillable="true" abstract="false" />
  <xsd:element id="zfgn_StockIssuedDuringPeriodValueStockOptionsExercisedAndEmployeeStockPurchasePlan" name="StockIssuedDuringPeriodValueStockOptionsExercisedAndEmployeeStockPurchasePlan" type="xbrli:monetaryItemType" substitutionGroup="xbrli:item" xbrli:periodType="duration" nillable="true" abstract="false" xbrli:balance="credit" />
  <xsd:element id="zfgn_PremiumOnMarketableSecurities" name="PremiumOnMarketableSecurities" type="xbrli:monetaryItemType" substitutionGroup="xbrli:item" xbrli:periodType="duration" nillable="true" abstract="false" xbrli:balance="credit" />
  <xsd:element id="zfgn_IncreaseDecreaseInTaxIncentivesReceivable" name="IncreaseDecreaseInTaxIncentivesReceivable" type="xbrli:monetaryItemType" substitutionGroup="xbrli:item" xbrli:periodType="duration" nillable="true" abstract="false" xbrli:balance="credit" />
  <xsd:element id="zfgn_ScheduleOfAccruedLiabilitiesAndOtherLiabilitiesTableTextBlock" name="ScheduleOfAccruedLiabilitiesAndOtherLiabilitiesTableTextBlock" type="nonnum:textBlockItemType" substitutionGroup="xbrli:item" xbrli:periodType="duration" nillable="true" abstract="false" />
  <xsd:element id="zfgn_ScheduleOfNotesPayableTableTextBlock" name="ScheduleOfNotesPayableTableTextBlock" type="nonnum:textBlockItemType" substitutionGroup="xbrli:item" xbrli:periodType="duration" nillable="true" abstract="false" />
  <xsd:element id="zfgn_ScheduleOfSupplementalBalanceSheetInformationRelatedToLeasesTableTextBlock" name="ScheduleOfSupplementalBalanceSheetInformationRelatedToLeasesTableTextBlock" type="nonnum:textBlockItemType" substitutionGroup="xbrli:item" xbrli:periodType="duration" nillable="true" abstract="false" />
  <xsd:element id="zfgn_ScheduleOfWeightedAverageRemainingLeaseTermAndWeightedAverageDiscountRateOfOperatingLeasesTableTextBlock" name="ScheduleOfWeightedAverageRemainingLeaseTermAndWeightedAverageDiscountRateOfOperatingLeasesTableTextBlock" type="nonnum:textBlockItemType" substitutionGroup="xbrli:item" xbrli:periodType="duration" nillable="true" abstract="false" />
  <xsd:element id="zfgn_OrganizationConsolidationAndPresentationOfFinancialStatementsDisclosureLineItems" name="OrganizationConsolidationAndPresentationOfFinancialStatementsDisclosureLineItems" type="xbrli:stringItemType" substitutionGroup="xbrli:item" xbrli:periodType="duration" nillable="true" abstract="true" />
  <xsd:element id="zfgn_OrganizationConsolidationAndPresentationOfFinancialStatementsDisclosureTable" name="OrganizationConsolidationAndPresentationOfFinancialStatementsDisclosureTable" type="xbrli:stringItemType" substitutionGroup="xbrldt:hypercubeItem" xbrli:periodType="duration" nillable="true" abstract="true" />
  <xsd:element id="zfgn_FollowOnOfferingsMember" name="FollowOnOfferingsMember" type="nonnum:domainItemType" substitutionGroup="xbrli:item" xbrli:periodType="duration" nillable="true" abstract="true" />
  <xsd:element id="zfgn_TermLoanMember" name="TermLoanMember" type="nonnum:domainItemType" substitutionGroup="xbrli:item" xbrli:periodType="duration" nillable="true" abstract="true" />
  <xsd:element id="zfgn_NetProceedsFromSaleOfSecurities" name="NetProceedsFromSaleOfSecurities" type="xbrli:monetaryItemType" substitutionGroup="xbrli:item" xbrli:periodType="duration" nillable="true" abstract="false" xbrli:balance="debit" />
  <xsd:element id="zfgn_AccruedResearchAndDevelopmentExpenseCurrent" name="AccruedResearchAndDevelopmentExpenseCurrent" type="xbrli:monetaryItemType" substitutionGroup="xbrli:item" xbrli:periodType="instant" nillable="true" abstract="false" xbrli:balance="credit" />
  <xsd:element id="zfgn_DebtInstrumentFeePercentage" name="DebtInstrumentFeePercentage" type="num:percentItemType" substitutionGroup="xbrli:item" xbrli:periodType="duration" nillable="true" abstract="false" />
  <xsd:element id="zfgn_RestrictedCashAndInvestmentsAsPercentageOfOutstandingPrincipalAmount" name="RestrictedCashAndInvestmentsAsPercentageOfOutstandingPrincipalAmount" type="num:percentItemType" substitutionGroup="xbrli:item" xbrli:periodType="duration" nillable="true" abstract="false" />
  <xsd:element id="zfgn_CashCashEquivalentsAndShortTermInvestmentsPercentage" name="CashCashEquivalentsAndShortTermInvestmentsPercentage" type="num:percentItemType" substitutionGroup="xbrli:item" xbrli:periodType="instant" nillable="true" abstract="false" />
  <xsd:element id="zfgn_PercentageOfPrincipalBalanceToBeSecuredInRestrictedCashAccount" name="PercentageOfPrincipalBalanceToBeSecuredInRestrictedCashAccount" type="num:percentItemType" substitutionGroup="xbrli:item" xbrli:periodType="duration" nillable="true" abstract="false" />
  <xsd:element id="zfgn_DebtInstrumentRestrictiveCovenantsInvestmentInSubsidiaries" name="DebtInstrumentRestrictiveCovenantsInvestmentInSubsidiaries" type="xbrli:monetaryItemType" substitutionGroup="xbrli:item" xbrli:periodType="duration" nillable="true" abstract="false" xbrli:balance="debit" />
  <xsd:element id="zfgn_LineOfCreditFacilityDebtDefaultMinimumAmount" name="LineOfCreditFacilityDebtDefaultMinimumAmount" type="xbrli:monetaryItemType" substitutionGroup="xbrli:item" xbrli:periodType="instant" nillable="true" abstract="false" xbrli:balance="credit" />
  <xsd:element id="zfgn_LongTermNotesPayableBeforeAccretion" name="LongTermNotesPayableBeforeAccretion" type="xbrli:monetaryItemType" substitutionGroup="xbrli:item" xbrli:periodType="instant" nillable="true" abstract="false" xbrli:balance="credit" />
  <xsd:element id="zfgn_TwoThousandFourteenStockOptionMember" name="TwoThousandFourteenStockOptionMember" type="nonnum:domainItemType" substitutionGroup="xbrli:item" xbrli:periodType="duration" nillable="true" abstract="true" />
  <xsd:element id="zfgn_TwoThousandAndFourteenEmployeeStockPurchasePlanMember" name="TwoThousandAndFourteenEmployeeStockPurchasePlanMember" type="nonnum:domainItemType" substitutionGroup="xbrli:item" xbrli:periodType="duration" nillable="true" abstract="true" />
  <xsd:element id="zfgn_AreaOfOfficeSpace" name="AreaOfOfficeSpace" type="num:areaItemType" substitutionGroup="xbrli:item" xbrli:periodType="duration" nillable="true" abstract="false" />
  <xsd:element id="zfgn_BostonMember" name="BostonMember" type="nonnum:domainItemType" substitutionGroup="xbrli:item" xbrli:periodType="duration" nillable="true" abstract="true" />
  <xsd:element id="zfgn_ShigoCenterPlazaOwnersLLCMember" name="ShigoCenterPlazaOwnersLLCMember" type="nonnum:domainItemType" substitutionGroup="xbrli:item" xbrli:periodType="duration" nillable="true" abstract="true" />
  <xsd:element id="zfgn_OfficeSpaceLeaseMember" name="OfficeSpaceLeaseMember" type="nonnum:domainItemType" substitutionGroup="xbrli:item" xbrli:periodType="duration" nillable="true" abstract="true" />
  <xsd:element id="zfgn_AdditionalOfficeSpaceMember" name="AdditionalOfficeSpaceMember" type="nonnum:domainItemType" substitutionGroup="xbrli:item" xbrli:periodType="duration" nillable="true" abstract="true" />
  <xsd:element id="zfgn_AdditionalOfficeSpaceTwoMember" name="AdditionalOfficeSpaceTwoMember" type="nonnum:domainItemType" substitutionGroup="xbrli:item" xbrli:periodType="duration" nillable="true" abstract="true" />
  <xsd:element id="zfgn_UnrelatedThirdPartyMember" name="UnrelatedThirdPartyMember" type="nonnum:domainItemType" substitutionGroup="xbrli:item" xbrli:periodType="duration" nillable="true" abstract="true" />
  <xsd:element id="zfgn_PreCommercializationMilestonesMember" name="PreCommercializationMilestonesMember" type="nonnum:domainItemType" substitutionGroup="xbrli:item" xbrli:periodType="duration" nillable="true" abstract="true" />
  <xsd:element id="zfgn_ProductCommercializationMilestonesMember" name="ProductCommercializationMilestonesMember" type="nonnum:domainItemType" substitutionGroup="xbrli:item" xbrli:periodType="duration" nillable="true" abstract="true" />
  <xsd:element id="zfgn_SubsequentLicensedProductMember" name="SubsequentLicensedProductMember" type="nonnum:domainItemType" substitutionGroup="xbrli:item" xbrli:periodType="duration" nillable="true" abstract="true" />
  <xsd:element id="zfgn_DevelopmentBasedMilestonesMember" name="DevelopmentBasedMilestonesMember" type="nonnum:domainItemType" substitutionGroup="xbrli:item" xbrli:periodType="duration" nillable="true" abstract="true" />
  <xsd:element id="zfgn_OperatingLeasesNumberOfOptionsToExtendLease" name="OperatingLeasesNumberOfOptionsToExtendLease" type="xbrli:integerItemType" substitutionGroup="xbrli:item" xbrli:periodType="duration" nillable="true" abstract="false" />
  <xsd:element id="zfgn_SubleaseAreaOfRealEstateProperty" name="SubleaseAreaOfRealEstateProperty" type="num:areaItemType" substitutionGroup="xbrli:item" xbrli:periodType="instant" nillable="true" abstract="false" />
  <xsd:element id="zfgn_SubleaseExpirationDate" name="SubleaseExpirationDate" type="xbrli:dateItemType" substitutionGroup="xbrli:item" xbrli:periodType="duration" nillable="true" abstract="false" />
  <xsd:element id="zfgn_MilestonePaymentAmount" name="MilestonePaymentAmount" type="xbrli:monetaryItemType" substitutionGroup="xbrli:item" xbrli:periodType="instant" nillable="true" abstract="false" xbrli:balance="credit" />
  <xsd:element id="zfgn_LicensingFeesPerProductMaximum" name="LicensingFeesPerProductMaximum" type="xbrli:monetaryItemType" substitutionGroup="xbrli:item" xbrli:periodType="instant" nillable="true" abstract="false" xbrli:balance="credit" />
  <xsd:element id="zfgn_MilestoneLiability" name="MilestoneLiability" type="xbrli:monetaryItemType" substitutionGroup="xbrli:item" xbrli:periodType="instant" nillable="true" abstract="false" xbrli:balance="credit" />
  <xsd:element id="zfgn_Retirement401KPlanMember" name="Retirement401KPlanMember" type="nonnum:domainItemType" substitutionGroup="xbrli:item" xbrli:periodType="duration" nillable="true" abstract="true" />
  <xsd:element id="zfgn_EffectiveTaxIncentiveRateRelatedToResearchAndDevelopment" name="EffectiveTaxIncentiveRateRelatedToResearchAndDevelopment" type="num:percentItemType" substitutionGroup="xbrli:item" xbrli:periodType="duration" nillable="true" abstract="false" />
  <xsd:element id="zfgn_TaxIncentiveResearchAndDevelopmentActivities" name="TaxIncentiveResearchAndDevelopmentActivities" type="xbrli:monetaryItemType" substitutionGroup="xbrli:item" xbrli:periodType="duration" nillable="true" abstract="false" xbrli:balance="credit" />
  <xsd:element id="zfgn_PercentageReductionResearchAndDevelopmentCosts" name="PercentageReductionResearchAndDevelopmentCosts" type="num:percentItemType" substitutionGroup="xbrli:item" xbrli:periodType="duration" nillable="true" abstract="false" />
  <xsd:element id="zfgn_TaxIncentiveReceivable" name="TaxIncentiveReceivable" type="xbrli:monetaryItemType" substitutionGroup="xbrli:item" xbrli:periodType="instant" nillable="true" abstract="false" xbrli:balance="debit" />
  <xsd:element id="zfgn_ResearchAndDevelopmentTaxIncentiveLineItems" name="ResearchAndDevelopmentTaxIncentiveLineItems" type="xbrli:stringItemType" substitutionGroup="xbrli:item" xbrli:periodType="duration" nillable="true" abstract="true" />
  <xsd:element id="zfgn_ResearchAndDevelopmentExpensesTable" name="ResearchAndDevelopmentExpensesTable" type="xbrli:stringItemType" substitutionGroup="xbrldt:hypercubeItem" xbrli:periodType="duration" nillable="true" abstract="true" />
</xsd:schema>
