The epidermal growth factor receptor (EGFR) plays an important role in cell growth, differentiation, and survival. Targeting EGFR in patients with colorectal cancer has become an important therapeutic tool. Recently, a monoclonal antibody against the extracellular domain of the receptor (cetuximab [Erbitux]) has been approved for the treatment of patients with EGFR-positive metastatic disease refractory to irinotecan (Camptosar)-based therapy. The role of other targeted agents against EGFR, including other monoclonal antibodies as well as inhibitors of the intracellular tyrosine kinase domain, will also be discussed.