Epidermal growth factor receptor (EGFR) has been validated as an important target in the treatment of metastatic colorectal cancer (mCRC). While initial studies focused on the treatment of disease that was refractory to available chemotherapy agents, 2 recent themes have emerged: the use of KRAS mutation status to select those who will benefit from anti-EGFR therapy, and the movement of these agents to earlier "lines" of therapy. We review the use of the EGFR-targeted monoclonal antibodies cetuximab and panitumumab in mCRC including the incorporation of KRAS testing in patients, and also review the use of prophylactic therapy for skin toxicity associated with EGFR-targeted therapies.