Novel targeted agents increase the therapeutic armamentarium in metastatic colorectal cancer (mCRC). Monoclonal antibodies against the epidermal growth factor receptor (EGFR) are active against EGFR-expressing mCRC that is refractory to irinotecan. EGFR monoclonal antibodies also have promise in less advanced stages of CRC. Cetuximab and panitumumab are clearly active agents. It has been shown that cetuximab is more active when administered in combination with irinotecan. Phase II studies also report promising activity when monoclonal antibodies against the EGFR are combined with classic chemotherapeutic regimens in the first-line treatment of mCRC. However, the best means of scheduling such agents and integrating them with each other and with chemotherapy have yet to be established. The management of toxicity (particularly rash) and finding appropriate means of selecting patients pose additional challenges. While the occurrence of rash is associated with greater likelihood of response, EGFR staining by immunohistochemistry at baseline is not. For reasons that are not yet clear, the tyrosine kinase inhibitors of EGFR seem less effective than their monoclonal antibody counterparts in the therapy of mCRC.