We hypothesized that co-targeting the epidermal growth factor receptor (EGFR) and Src with the EGFR inhibitor gefitinib and the Src inhibitor AZD0530 would increase growth inhibition and impede migration. Cells overexpressing EGFR were more sensitive to gefitinib than cells expressing mutated EGFR or normal levels of wild-type EGFR. Furthermore, cells with mutated EGFR responded to low doses of gefitinib with increased proliferation. AZD0530 was an effective inhibitor of proliferation and migration, irrespective of EGFR status. These results suggest that co-targeting EGFR and Src might be a valuable treatment approach for malignancies associated with altered expression of EGFR, EGFRvIII, and/or Src.