<?xml version="1.0" encoding="UTF-8"?>

<!--XBRL Document Created with Wdesk from Workiva-->
<!--Copyright 2023 Workiva-->
<!--r:8affbca6-9137-4e9b-af8e-1de71c3857ee,g:4c087888-7dc5-4846-a79b-fd5a019589a3-->
<link:linkbase xmlns:link="http://www.xbrl.org/2003/linkbase" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" 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">
  <link:arcroleRef arcroleURI="http://xbrl.org/int/dim/arcrole/all" xlink:type="simple" xlink:href="http://www.xbrl.org/2005/xbrldt-2005.xsd#all"/>
  <link:arcroleRef arcroleURI="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:type="simple" xlink:href="http://www.xbrl.org/2005/xbrldt-2005.xsd#hypercube-dimension"/>
  <link:arcroleRef arcroleURI="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:type="simple" xlink:href="http://www.xbrl.org/2005/xbrldt-2005.xsd#dimension-default"/>
  <link:arcroleRef arcroleURI="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:type="simple" xlink:href="http://www.xbrl.org/2005/xbrldt-2005.xsd#dimension-domain"/>
  <link:arcroleRef arcroleURI="http://xbrl.org/int/dim/arcrole/domain-member" xlink:type="simple" xlink:href="http://www.xbrl.org/2005/xbrldt-2005.xsd#domain-member"/>
  <link:roleRef roleURI="http://sema4.com/role/DocumentandEntityInformationDocument" xlink:type="simple" xlink:href="smfr-20230109.xsd#DocumentandEntityInformationDocument"/>
  <link:definitionLink xlink:role="http://sema4.com/role/DocumentandEntityInformationDocument" xlink:type="extended" id="ibf3dca89cde746b4855a1992b7409ea9_DocumentandEntityInformationDocument">
    <link:loc xlink:type="locator" xlink:label="loc_dei_EntityInformationLineItems_e2b114ef-46e5-48f4-ba06-b50e7992d351" xlink:href="https://xbrl.sec.gov/dei/2021/dei-2021.xsd#dei_EntityInformationLineItems"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_DocumentType_3e14fd32-23cc-4d51-b510-259ad308bf33" xlink:href="https://xbrl.sec.gov/dei/2021/dei-2021.xsd#dei_DocumentType"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_dei_EntityInformationLineItems_e2b114ef-46e5-48f4-ba06-b50e7992d351" xlink:to="loc_dei_DocumentType_3e14fd32-23cc-4d51-b510-259ad308bf33" xlink:type="arc" order="0"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_DocumentPeriodEndDate_1ab6bf35-c75d-4dbf-b867-c5377ef77d3e" xlink:href="https://xbrl.sec.gov/dei/2021/dei-2021.xsd#dei_DocumentPeriodEndDate"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_dei_EntityInformationLineItems_e2b114ef-46e5-48f4-ba06-b50e7992d351" xlink:to="loc_dei_DocumentPeriodEndDate_1ab6bf35-c75d-4dbf-b867-c5377ef77d3e" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_EntityRegistrantName_393da741-eec7-4c4a-acad-33bed7ec2041" xlink:href="https://xbrl.sec.gov/dei/2021/dei-2021.xsd#dei_EntityRegistrantName"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_dei_EntityInformationLineItems_e2b114ef-46e5-48f4-ba06-b50e7992d351" xlink:to="loc_dei_EntityRegistrantName_393da741-eec7-4c4a-acad-33bed7ec2041" xlink:type="arc" order="2"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_EntityCentralIndexKey_6ea5b57d-bb98-4081-a78a-da2c60956295" xlink:href="https://xbrl.sec.gov/dei/2021/dei-2021.xsd#dei_EntityCentralIndexKey"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_dei_EntityInformationLineItems_e2b114ef-46e5-48f4-ba06-b50e7992d351" xlink:to="loc_dei_EntityCentralIndexKey_6ea5b57d-bb98-4081-a78a-da2c60956295" xlink:type="arc" order="3"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_CurrentFiscalYearEndDate_ad499b6e-4da7-45a8-b136-c465ab1754a5" xlink:href="https://xbrl.sec.gov/dei/2021/dei-2021.xsd#dei_CurrentFiscalYearEndDate"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_dei_EntityInformationLineItems_e2b114ef-46e5-48f4-ba06-b50e7992d351" xlink:to="loc_dei_CurrentFiscalYearEndDate_ad499b6e-4da7-45a8-b136-c465ab1754a5" xlink:type="arc" order="4"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_AmendmentFlag_b4432cf9-679e-4a19-9202-6943a40ca66b" xlink:href="https://xbrl.sec.gov/dei/2021/dei-2021.xsd#dei_AmendmentFlag"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_dei_EntityInformationLineItems_e2b114ef-46e5-48f4-ba06-b50e7992d351" xlink:to="loc_dei_AmendmentFlag_b4432cf9-679e-4a19-9202-6943a40ca66b" xlink:type="arc" order="5"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_EntityIncorporationStateCountryCode_e94698e4-c124-4472-93f6-e9b88e4533d1" xlink:href="https://xbrl.sec.gov/dei/2021/dei-2021.xsd#dei_EntityIncorporationStateCountryCode"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_dei_EntityInformationLineItems_e2b114ef-46e5-48f4-ba06-b50e7992d351" xlink:to="loc_dei_EntityIncorporationStateCountryCode_e94698e4-c124-4472-93f6-e9b88e4533d1" xlink:type="arc" order="6"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_EntityFileNumber_472b919f-fc86-44cf-9d57-9ad69df1c9a3" xlink:href="https://xbrl.sec.gov/dei/2021/dei-2021.xsd#dei_EntityFileNumber"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_dei_EntityInformationLineItems_e2b114ef-46e5-48f4-ba06-b50e7992d351" xlink:to="loc_dei_EntityFileNumber_472b919f-fc86-44cf-9d57-9ad69df1c9a3" xlink:type="arc" order="7"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_EntityTaxIdentificationNumber_7b599ed9-78a0-496d-bd89-930ebdb0c8e4" xlink:href="https://xbrl.sec.gov/dei/2021/dei-2021.xsd#dei_EntityTaxIdentificationNumber"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_dei_EntityInformationLineItems_e2b114ef-46e5-48f4-ba06-b50e7992d351" xlink:to="loc_dei_EntityTaxIdentificationNumber_7b599ed9-78a0-496d-bd89-930ebdb0c8e4" xlink:type="arc" order="8"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_EntityAddressAddressLine1_b08b1f56-f7c5-46bb-9dd1-3f260074485b" xlink:href="https://xbrl.sec.gov/dei/2021/dei-2021.xsd#dei_EntityAddressAddressLine1"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_dei_EntityInformationLineItems_e2b114ef-46e5-48f4-ba06-b50e7992d351" xlink:to="loc_dei_EntityAddressAddressLine1_b08b1f56-f7c5-46bb-9dd1-3f260074485b" xlink:type="arc" order="9"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_EntityAddressCityOrTown_6be32182-908d-4359-9713-2147ea3032a8" xlink:href="https://xbrl.sec.gov/dei/2021/dei-2021.xsd#dei_EntityAddressCityOrTown"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_dei_EntityInformationLineItems_e2b114ef-46e5-48f4-ba06-b50e7992d351" xlink:to="loc_dei_EntityAddressCityOrTown_6be32182-908d-4359-9713-2147ea3032a8" xlink:type="arc" order="10"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_EntityAddressStateOrProvince_a4a66361-4871-4e81-b121-467046b203c6" xlink:href="https://xbrl.sec.gov/dei/2021/dei-2021.xsd#dei_EntityAddressStateOrProvince"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_dei_EntityInformationLineItems_e2b114ef-46e5-48f4-ba06-b50e7992d351" xlink:to="loc_dei_EntityAddressStateOrProvince_a4a66361-4871-4e81-b121-467046b203c6" xlink:type="arc" order="11"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_EntityAddressPostalZipCode_b2615d2f-bbea-4178-8abc-8332991cb7b5" xlink:href="https://xbrl.sec.gov/dei/2021/dei-2021.xsd#dei_EntityAddressPostalZipCode"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_dei_EntityInformationLineItems_e2b114ef-46e5-48f4-ba06-b50e7992d351" xlink:to="loc_dei_EntityAddressPostalZipCode_b2615d2f-bbea-4178-8abc-8332991cb7b5" xlink:type="arc" order="12"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_CityAreaCode_2fb71fb4-32b6-41ae-a710-fda50276de35" xlink:href="https://xbrl.sec.gov/dei/2021/dei-2021.xsd#dei_CityAreaCode"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_dei_EntityInformationLineItems_e2b114ef-46e5-48f4-ba06-b50e7992d351" xlink:to="loc_dei_CityAreaCode_2fb71fb4-32b6-41ae-a710-fda50276de35" xlink:type="arc" order="13"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_LocalPhoneNumber_386c33dd-200e-4981-8e4e-517a213c9378" xlink:href="https://xbrl.sec.gov/dei/2021/dei-2021.xsd#dei_LocalPhoneNumber"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_dei_EntityInformationLineItems_e2b114ef-46e5-48f4-ba06-b50e7992d351" xlink:to="loc_dei_LocalPhoneNumber_386c33dd-200e-4981-8e4e-517a213c9378" xlink:type="arc" order="14"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_WrittenCommunications_1ae6aa2a-9d15-46f4-b9e2-c31af5c36afd" xlink:href="https://xbrl.sec.gov/dei/2021/dei-2021.xsd#dei_WrittenCommunications"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_dei_EntityInformationLineItems_e2b114ef-46e5-48f4-ba06-b50e7992d351" xlink:to="loc_dei_WrittenCommunications_1ae6aa2a-9d15-46f4-b9e2-c31af5c36afd" xlink:type="arc" order="15"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_SolicitingMaterial_b5a28430-860b-45a4-bb21-c4ca8b8e4162" xlink:href="https://xbrl.sec.gov/dei/2021/dei-2021.xsd#dei_SolicitingMaterial"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_dei_EntityInformationLineItems_e2b114ef-46e5-48f4-ba06-b50e7992d351" xlink:to="loc_dei_SolicitingMaterial_b5a28430-860b-45a4-bb21-c4ca8b8e4162" xlink:type="arc" order="16"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_PreCommencementTenderOffer_3b2158dc-8f9a-4578-8b50-78ea71d3ce65" xlink:href="https://xbrl.sec.gov/dei/2021/dei-2021.xsd#dei_PreCommencementTenderOffer"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_dei_EntityInformationLineItems_e2b114ef-46e5-48f4-ba06-b50e7992d351" xlink:to="loc_dei_PreCommencementTenderOffer_3b2158dc-8f9a-4578-8b50-78ea71d3ce65" xlink:type="arc" order="17"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_PreCommencementIssuerTenderOffer_c2b6a39f-e9d4-41d1-8512-604ad2dd9733" xlink:href="https://xbrl.sec.gov/dei/2021/dei-2021.xsd#dei_PreCommencementIssuerTenderOffer"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_dei_EntityInformationLineItems_e2b114ef-46e5-48f4-ba06-b50e7992d351" xlink:to="loc_dei_PreCommencementIssuerTenderOffer_c2b6a39f-e9d4-41d1-8512-604ad2dd9733" xlink:type="arc" order="18"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_Security12bTitle_b39c4400-39bd-4f5e-bbd5-e6e06adcdc81" xlink:href="https://xbrl.sec.gov/dei/2021/dei-2021.xsd#dei_Security12bTitle"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_dei_EntityInformationLineItems_e2b114ef-46e5-48f4-ba06-b50e7992d351" xlink:to="loc_dei_Security12bTitle_b39c4400-39bd-4f5e-bbd5-e6e06adcdc81" xlink:type="arc" order="19"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_TradingSymbol_194e75fc-f57a-4d18-bdd3-c56e4dc84efe" xlink:href="https://xbrl.sec.gov/dei/2021/dei-2021.xsd#dei_TradingSymbol"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_dei_EntityInformationLineItems_e2b114ef-46e5-48f4-ba06-b50e7992d351" xlink:to="loc_dei_TradingSymbol_194e75fc-f57a-4d18-bdd3-c56e4dc84efe" xlink:type="arc" order="20"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_SecurityExchangeName_016dcbc2-f922-4138-b2e3-4e042df4ff7f" xlink:href="https://xbrl.sec.gov/dei/2021/dei-2021.xsd#dei_SecurityExchangeName"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_dei_EntityInformationLineItems_e2b114ef-46e5-48f4-ba06-b50e7992d351" xlink:to="loc_dei_SecurityExchangeName_016dcbc2-f922-4138-b2e3-4e042df4ff7f" xlink:type="arc" order="21"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_EntityEmergingGrowthCompany_ff719349-891b-4fee-a87f-40d81b372c02" xlink:href="https://xbrl.sec.gov/dei/2021/dei-2021.xsd#dei_EntityEmergingGrowthCompany"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_dei_EntityInformationLineItems_e2b114ef-46e5-48f4-ba06-b50e7992d351" xlink:to="loc_dei_EntityEmergingGrowthCompany_ff719349-891b-4fee-a87f-40d81b372c02" xlink:type="arc" order="22"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_EntityExTransitionPeriod_3b25a395-174a-4776-a9d4-393bce3ecf8a" xlink:href="https://xbrl.sec.gov/dei/2021/dei-2021.xsd#dei_EntityExTransitionPeriod"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_dei_EntityInformationLineItems_e2b114ef-46e5-48f4-ba06-b50e7992d351" xlink:to="loc_dei_EntityExTransitionPeriod_3b25a395-174a-4776-a9d4-393bce3ecf8a" xlink:type="arc" order="23"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_EntitiesTable_aed5a934-cfa7-4124-ab98-80e44de2b627" xlink:href="https://xbrl.sec.gov/dei/2021/dei-2021.xsd#dei_EntitiesTable"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/all" xlink:from="loc_dei_EntityInformationLineItems_e2b114ef-46e5-48f4-ba06-b50e7992d351" xlink:to="loc_dei_EntitiesTable_aed5a934-cfa7-4124-ab98-80e44de2b627" xlink:type="arc" order="1" xbrldt:closed="true" xbrldt:contextElement="segment"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_StatementEquityComponentsAxis_6ec13c7c-fdae-488b-9322-12992b3f45e4" xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_StatementEquityComponentsAxis"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="loc_dei_EntitiesTable_aed5a934-cfa7-4124-ab98-80e44de2b627" xlink:to="loc_us-gaap_StatementEquityComponentsAxis_6ec13c7c-fdae-488b-9322-12992b3f45e4" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_EquityComponentDomain_6ec13c7c-fdae-488b-9322-12992b3f45e4_default" xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_EquityComponentDomain"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="loc_us-gaap_StatementEquityComponentsAxis_6ec13c7c-fdae-488b-9322-12992b3f45e4" xlink:to="loc_us-gaap_EquityComponentDomain_6ec13c7c-fdae-488b-9322-12992b3f45e4_default" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_EquityComponentDomain_07d6ce22-3845-4690-8609-e07a2f940dfa" xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_EquityComponentDomain"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="loc_us-gaap_StatementEquityComponentsAxis_6ec13c7c-fdae-488b-9322-12992b3f45e4" xlink:to="loc_us-gaap_EquityComponentDomain_07d6ce22-3845-4690-8609-e07a2f940dfa" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_CommonStockMember_ca9751e8-2bf0-41d2-aee9-392c030eabfb" xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_CommonStockMember"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_EquityComponentDomain_07d6ce22-3845-4690-8609-e07a2f940dfa" xlink:to="loc_us-gaap_CommonStockMember_ca9751e8-2bf0-41d2-aee9-392c030eabfb" xlink:type="arc" order="0"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_WarrantMember_086ce19f-bdc1-4a41-a901-3ea6a36edf7a" xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_WarrantMember"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_us-gaap_EquityComponentDomain_07d6ce22-3845-4690-8609-e07a2f940dfa" xlink:to="loc_us-gaap_WarrantMember_086ce19f-bdc1-4a41-a901-3ea6a36edf7a" xlink:type="arc" order="1"/>
  </link:definitionLink>
</link:linkbase>
