In recent years, increasing amounts of trial data have become available indicating the clinical efficacy of epidermal growth factor receptor (EGFR)-targeted antibody therapy in the management of advanced colorectal cancer (CRC). These trial data have consistently demonstrated the modest single-agent activity of these agents when given in the chemorefractory setting and the potential ability for EGFR-targeted agents to reverse chemoresistance when given in combination with cytotoxic chemotherapy agents. In this article, we review the clinical development of EGFR-targeted therapies and discuss their current role in the management of patients with previously treated advanced CRC.