Abstract Cetuximab and panitumumab, monoclonal antibodies used to target the epidermal growth factor receptor (EGFR), were recently approved by the United States Food and Drug Administration for use as single agents or in combination with other chemotherapy drugs in the treatment of metastatic colorectal cancer. The anti-EGFR monoclonal antibodies, either as single agents or in combination with chemotherapy, have demonstrated clinical activity in this setting. When combined with standard cytotoxic chemotherapy or other targeted agents (e.g., bevacizumab, an anti-vascular endothelial growth factor monoclonal antibody), anti-EGFR monoclonal antibodies have been well tolerated and produced minimal toxicities. However, cetuximab and panitumumab appear to benefit only select patients. Predictive markers of efficacy, including EGFR overexpression, development of skin rash, and the absence of a K-ras mutation, have been evaluated in clinical studies to identify patients likely to respond to anti-EGFR monoclonal antibody therapy. This review discusses recent clinical studies of anti-EGFR monoclonal antibodies in the treatment of metastatic colorectal cancer, predictive markers of their efficacy, and common toxicities associated with their use.