The standard treatment of metastatic colorectal cancer (mCRC) is combination of 5- fluorouracil/folinic acid with irinotecan or oxaliplatin-based chemotherapy. Epidermal growth factor receptor (EGFR) is overexpressed in 70%-80% of colorectal cancers (CRC). EGFR overexpression is known to be involved in carcinogenic processes, such as cell proliferation, apoptosis, angiogenesis and metastasis. Monoclonal antibodies targeting EGFR have shown antitumor activity and improved the efficacy of chemotherapy. Cetuximab is a chimeric immunoglobulin (Ig) G1 anti-EGFR monoclonal antibody (MoAb). Several clinical studies have shown cetuximab, either as a single agent or in combination with irinotecan, having promising efficacy in patients with metastatic CRC. Cetuximab with 5-fluorouracil/LV (leucovorin) plus irinotecan or oxaliplatin-based chemotherapy has shown higher response rate and longer time to progression as first-line treatment of mCRC. Currently, there are no data showing that addition of cetuximab would prolong overall survival in randomized studies. Panitumumab, a fully human IgG2 monoclonal antibody, has also shown antitumor activity against EGFR-expressing mCRC with less allergic reaction. Anti-EGFR MoAbs are well tolerated and have limited overlapping toxicities in combination with other cytotoxic drugs. The most common side effect of anti-EGFR MoAb is an acneform skin rash, which is a surrogate marker of efficacy of treatment with MoAbs. In this review, we will discuss the use of anti-EGFR MoAbs in the treatment of mCRC, with focus on cetuximab and panitumumab.