Targeted mAbs to VEGFR and EGFR are well-established therapies for the treatment of colorectal cancer. The costs and toxicities associated with these novel treatments are not insignificant, and therefore molecular markers that predict treatment efficacy are needed to individualize the therapy administered to each patient. Recent data in this research field support KRAS mutation testing to guide the selection of EGFR inhibitors for the treatment of colorectal cancer. This review discusses the evidence that KRAS mutation analysis can indicate a beneficial response to EGFR inhibitors, and the potential and limitations of other mutations in the VEGF and EGF signaling pathways as predictive molecular markers in this setting.