Novel therapeutic agents that target the epidermal growth factor receptor (EGFR) constitute an important addition to the therapeutic armamentarium for the treatment of metastatic disease. EGFR-targeted agents currently approved by the U.S. Food and Drug Administration include cetuximab, a monoclonal antibody for the treatment of colorectal cancer; and the small-molecule EGFR tyrosine kinase inhibitor (TKI) erlotinib for the treatment of nonsmall cell lung cancer (NSCLC) and pancreatic cancer. Approval of the TKI gefitinib for NSCLC recently was withdrawn. Although both classes of anti-EGFR agents target the same receptor, substantial distinctions regarding their mechanism significantly affect dosing requirements, toxicity profiles, and their use as combination agents. Cancer 2006. © 2006 American Cancer Society.