Recent knowledge about the intermediate steps and final consequences of ligand-dependent epidermal growth factor receptor (EGFR) activation has clearly supported the notion that EGFR plays a fundamental role in regulating the proliferation and survival of malignant neoplasms. Among the rationally designed target-based therapeutics that are being assessed, those targeting EGFR appear to be some of the most clinically relevant. The strategy of using monoclonal antibodies (mAbs) to block ligand binding to the extracellular domain of the EGFR has led to the development of therapeutics that robustly arrest malignant cell proliferation and, in some cases, induce profound tumor regression. The chimeric mAb against EGFR, cetuximab, has already been approved by regulatory agencies worldwide to treat patients with advanced colorectal cancer. Other mAbs against EGFR, particularly panitumumab (ABX-EGF), h-R3, and EMD72000, are in advanced stages of clinical development.