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Purpose: Aberrant activation of the intracellular tyrosine kinase Src has been implicated as a mechanism of acquired chemotherapy resistance in metastatic colorectal cancer (mCRC). Here, the oral tyrosine kinase Src inhibitor, dasatinib, was investigated in combination with FOLFOX and cetuximab. Experimental Design: We performed a phase IB/II study of 77 patients with previously treated mCRC. Primary objectives were to determine the maximum tolerated dose, dose-limiting toxicities (DLT), pharmacodynamics, and efficacy. Using a 3 + 3 design, patients received FOLFOX6 with cetuximab and escalating doses of dasatinib (100, 150, 200 mg daily), followed by a 12-patient expansion cohort at 150 mg. Phase II studies evaluated FOLFOX plus dasatinib 100 mg in KRAS c12/13mut patients or in combination with cetuximab if KRAS c12/13WT. FAK and paxillin were utilized as surrogate blood biomarkers of Src inhibition, and paired biopsies of liver metastases were obtained in patients in the expansion cohort. Results: In phase IB, the DLTs were grade 3/4 fatigue (20%) and neutropenia (23%). In phase II, grade 3/4 fatigue (23%) and pleural effusions (11%) were present. Response rates were 20% (6 of 30) in the phase IB escalation and expansion cohort and 13% (3 of 24) and 0% (0 of 23) in the KRAS c12/13WT and mutant cohorts of phase II, respectively. Median progression-free survival was 4.6, 2.3, and 2.3 months, respectively. There was no evidence of Src inhibition based on surrogate blood biomarkers or paired tumor biopsies. Conclusions: The combination of dasatinib plus FOLFOX with or without cetuximab showed only modest clinical activity in refractory colorectal cancer. This appears to be primarily due to a failure to fully inhibit Src at the achievable doses of dasatinib. The combination of dasatinib plus FOLFOX with or without cetuximab did not show meaningful clinical activity in refractory colorectal cancer due to failure to fully inhibit Src. Clin Cancer Res; 23(15); 4146–54. ©2017 AACR.