Compelling experimental and clinical evidence suggests that epidermal growth factor receptor (EGFR) plays an important role in the pathogenesis of a variety of human cancers; thus, providing a strong rationale for the development of receptor antagonists as effective and specific therapeutic strategies for the treatment of EGFR-expressing cancers. Monoclonal antibodies (mAb), owing to their high specificity towards a given target, represent a unique class of novel cancer therapeutics. A number of anti-EGFR mAb are currently being developed in our clinic, including two that have been approved by the United States Food and Drug Administration for the treatment of refractory metastatic colorectal cancer (mCRC) and squamous cell carcinomas of the head and neck (SCCHN). Cetuximab (Erbitux, IMC-C225), an IgG 1 mAb, has demonstrated significant antitumor activity,both as a single agent and in combination with chemotherapeutics and radiation,in patients with refractory mCRC and SCCHN, respectively. Panitumumab(Vectibix), an IgG2 mAb, has been approved as a single agent for the treatment of patients with refractory mCRC. These mAb, via blocking ligand/receptor interactions, exert their biological activity via multiple mechanisms, includinginhibition of cell cycle progression, potentiation of cell apoptosis, inhibition of DNA repair, inhibition of angiogenesis, tumor cell invasion and metastasis and,potentially, induction of immunological effector mechanisms. Anti-EGFR anti-bodies have demonstrated good safety profiles and potent anticancer activity in our clinic and may prove to be efficacious agents in the treatment of a variety of human malignancies.