The epidermal growth factor receptor (EGFR) is overexpressed in as many as 77% of colorectal cancer (CRC) cases. The EGFR is known to be involved in carcinogenetic processes such as cell proliferation, apoptosis, angiogenesis, cell motility, and metastasis. Preclinical and clinical studies have shown that targeting EGFR is a valid strategy for anticancer therapy. Currently, 2 classes of anti-EGFR agents are in phase II/III clinical development: monoclonal antibodies and tyrosine kinase (TK) inhibitors. The most established monoclonal antibody is cetuximab, the only EGFR inhibitor that is currently approved for use in patients with metastatic CRC. Several clinical studies of cetuximab, as a single agent or in combination with irinotecan, have shown promising efficacy in patients with metastatic CRC. Two other monoclonal antibodies, matuzumab (EMD 72000) and panitumumab (ABG-EGF), also have shown activity against EGFR-expressing CRC but are still in the early stage of clinical development. The activity of the EGFR TK inhibitors erlotinib and gefitinib have already been investigated in clinical phase III trials in patients with non-small-lung cancer, suggesting that sequential rather than concurrent erlotinib/gefitinib-based treatment provides a benefit in clinical outcome. The EGFR-targeting agents are reasonably well tolerated and have limited overlapping toxicities in combination with other cytotoxic drugs. The most common side effect of anti-EGFR treatment is an acneiform skin rash, which is associated with the clinical outcome of treatment with monoclonal antibodies and TK inhibitors. Future clinical studies are needed to establish these EGFR-targeting agents in anticancer treatment to investigate efficacy of therapies combining EGFR-targeted agents with other targeting agents and to describe additional markers determining the clinical outcome of anti-EGFR therapy.