<?xml version="1.0" encoding="us-ascii"?><InstanceReport xmlns:xsd="http://www.w3.org/2001/XMLSchema" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"><Version>2.4.0.8</Version><ReportLongName>118 - Disclosure - Significant Contractual Service and Milestone Agreements</ReportLongName><DisplayLabelColumn>true</DisplayLabelColumn><ShowElementNames>false</ShowElementNames><RoundingOption /><HasEmbeddedReports>false</HasEmbeddedReports><Columns><Column FlagID="0"><Id>1</Id><IsAbstractGroupTitle>false</IsAbstractGroupTitle><LabelSeparator>

</LabelSeparator><CurrencyCode /><FootnoteIndexer /><hasSegments>false</hasSegments><hasScenarios>false</hasScenarios><MCU><KeyName /><CurrencySymbol /><contextRef><ContextID>eol_PE10315---13S-1-0008_STD_366_20121231_0</ContextID><EntitySchema>http://www.sec.gov/CIK</EntitySchema><EntityValue>0001069308</EntityValue><PeriodDisplayName /><PeriodType>duration</PeriodType><PeriodStartDate>2012-01-01T00:00:00</PeriodStartDate><PeriodEndDate>2012-12-31T00:00:00</PeriodEndDate><Segments /><Scenarios /></contextRef><UPS /><CurrencyCode /><OriginalCurrencyCode /></MCU><CurrencySymbol /><Labels><Label Key="CalendarSupplement" Id="0" Label="12 Months Ended" /><Label Key="Calendar" Id="1" Label="Dec. 31, 2012" /></Labels></Column></Columns><Rows><Row FlagID="0"><Id>1</Id><IsAbstractGroupTitle>false</IsAbstractGroupTitle><LabelSeparator>

</LabelSeparator><Level>4</Level><ElementName>us-gaap_BusinessAndContractualArrangementsDisclosureTextBlock</ElementName><ElementPrefix>us-gaap_</ElementPrefix><IsBaseElement>true</IsBaseElement><BalanceType>na</BalanceType><PeriodType>duration</PeriodType><IsReportTitle>false</IsReportTitle><IsSegmentTitle>false</IsSegmentTitle><IsCalendarTitle>false</IsCalendarTitle><IsEquityPrevioslyReportedAsRow>false</IsEquityPrevioslyReportedAsRow><IsEquityAdjustmentRow>false</IsEquityAdjustmentRow><IsBeginningBalance>false</IsBeginningBalance><IsEndingBalance>false</IsEndingBalance><IsReverseSign>false</IsReverseSign><PreferredLabelRole>terseLabel</PreferredLabelRole><FootnoteIndexer /><Cells><Cell FlagID="0" ContextID="eol_PE10315---13S-1-0008_STD_366_20121231_0" UnitID=""><Id>1</Id><IsNumeric>false</IsNumeric><IsRatio>false</IsRatio><DisplayZeroAsNone>false</DisplayZeroAsNone><NumericAmount>0</NumericAmount><RoundedNumericAmount>0</RoundedNumericAmount><NonNumbericText>&lt;div&gt;
&lt;p style="MARGIN-TOP: 0px; MARGIN-BOTTOM: 0px"&gt;&lt;font style="FONT-FAMILY: Times New Roman" size="2"&gt;&lt;b&gt;Note 10. Significant
Contractual Service and Milestone Agreements&lt;/b&gt;&lt;/font&gt;&lt;/p&gt;
&lt;p style="MARGIN-TOP: 6px; TEXT-INDENT: 4%; MARGIN-BOTTOM: 0px"&gt;
&lt;font style="FONT-FAMILY: Times New Roman" size="2"&gt;In February
2012, Opexa entered into an agreement with Pharmaceutical Research
Associates, Inc. (&amp;#x201C;PRA&amp;#x201D;), a contract research
organization, in which PRA will provide Opexa with services related
to the design, implementation and management of Opexa&amp;#x2019;s
ongoing Phase IIb clinical trial program in SPMS (the &amp;#x201C;PRA
Agreement&amp;#x201D;). Under the terms of the PRA Agreement, Opexa made
upfront cash payments to PRA of $543,766. Future payments by Opexa
to PRA under the PRA Agreement are based on the achievement of
certain time and performance milestones as presented in the PRA
Agreement. In December 2012, Opexa entered into an Amendment #1 to
Task Order #1 (the &amp;#x201C;Amendment&amp;#x201D;) with PRA in which Opexa
agreed to reimburse PRA for additional services and pass-through
expenses incurred while performing out-of-scope work. Under the
terms of the Amendment, an upfront cash payment of $37,605 is to be
made to PRA as payment for certain out-of-scope tasks performed by
PRA and future payments by Opexa to PRA under the PRA Agreement on
the achievement of certain time milestones in the Amendment. Total
payments to PRA during 2012, which were charged to expense,
amounted to $1,382,236. Unless terminated by either party without
cause on 60 days prior notice or on shorter notice with cause, the
initial term of the PRA Agreement is for four years and
automatically renews for successive one year terms.&lt;/font&gt;&lt;/p&gt;
&lt;p style="MARGIN-TOP: 12px; TEXT-INDENT: 4%; MARGIN-BOTTOM: 0px"&gt;
&lt;font style="FONT-FAMILY: Times New Roman" size="2"&gt;During 2012,
Opexa entered into individual Clinical Trial Agreements with 18
clinical institutions (the &amp;#x201C;Institutions&amp;#x201D;) across the
U.S. and 18 principal investigators (the
&amp;#x201C;Investigators&amp;#x201D;) acting within their employment or
agent positions within their clinical institution. Under the terms
of each Clinical Trial Agreement, each of the Investigators will
identify and recruit subjects with SPMS meeting certain enrollment
requirements and conduct clinical research in conjunction with
Opexa&amp;#x2019;s Phase IIb clinical study, and each of the
Institutions will provide appropriate resources and facilities so
the Institution&amp;#x2019;s Investigator can conduct Opexa&amp;#x2019;s
Phase IIb clinical study in a timely and professional manner and
according to the terms of the Clinical Trial Agreement. Under the
terms of each Clinical Trial Agreement, Opexa paid an upfront cash
payment to each Institution for start-up and other costs which were
charged directly to expense. Future payments by Opexa to the
Institutions during the term of each Clinical Trial Agreement are
based on the achievement of certain performance milestones as
presented in each Clinical Trial Agreement. Unless terminated by
Opexa without cause with 30 days&amp;#x2019; notice, or unless
terminated by the Institution, Investigator or Opexa for health or
safety reasons, the initial term of the Clinical Trial Agreements
with each Institution and Investigator is for the duration of their
enrolled subjects in the Phase IIb clinical study.&lt;/font&gt;&lt;/p&gt;
&lt;/div&gt;</NonNumbericText><FootnoteIndexer /><CurrencyCode /><CurrencySymbol /><IsIndependantCurrency>false</IsIndependantCurrency><ShowCurrencySymbol>false</ShowCurrencySymbol><DisplayDateInUSFormat>false</DisplayDateInUSFormat></Cell></Cells><ElementDataType>nonnum:textBlockItemType</ElementDataType><SimpleDataType>na</SimpleDataType><ElementDefenition>The entire disclosure for prepaid health care service provider's significant business and contractual arrangements with hospitals, physicians, or other associated entities.</ElementDefenition><ElementReferences>Reference 1: http://www.xbrl.org/2003/role/presentationRef

 -Publisher FASB

 -Name Accounting Standards Codification

 -Topic 954

 -SubTopic 405

 -Section 50

 -Paragraph 2

 -URI http://asc.fasb.org/extlink&amp;oid=6491204&amp;loc=d3e4879-115612



</ElementReferences><IsTotalLabel>false</IsTotalLabel><UnitID>0</UnitID><Label>Significant Contractual Service and Milestone Agreements</Label></Row></Rows><Footnotes /><IsEquityReport>false</IsEquityReport><ReportName>Significant Contractual Service and Milestone Agreements</ReportName><MonetaryRoundingLevel>UnKnown</MonetaryRoundingLevel><SharesRoundingLevel>UnKnown</SharesRoundingLevel><PerShareRoundingLevel>UnKnown</PerShareRoundingLevel><ExchangeRateRoundingLevel>UnKnown</ExchangeRateRoundingLevel><HasCustomUnits>true</HasCustomUnits><IsEmbedReport>false</IsEmbedReport><IsMultiCurrency>false</IsMultiCurrency><ReportType>Sheet</ReportType><RoleURI>http://www.opexatherapeutics.com/taxonomy/role/NotesToFinancialStatementsBusinessAndContractualArrangementsDisclosureTextBlock</RoleURI><NumberOfCols>1</NumberOfCols><NumberOfRows>1</NumberOfRows></InstanceReport>
