Cetuximab, an IgG1 chimeric monoclonal antibody directed against the epidermal growth factor receptor (EGFR), has been shown to have antitumor activity against EGFR-expressing colorectal cancer (CRC). Although the activity of cetuximab monotherapy is notable,cetuximab-based combinations have conferred greater benefit, with two-fold higher response rates and nearly three-fold longer progression free-survival with cetuximab plus irinotecan compared with cetuximab alone,even in irinotecan-refractory patients. Cetuximab monotherapy should be reserved for patients who cannot tolerate combination therapy. Interestingly, consistent with other reports of both EGFR-targeting antibodies and receptor tyrosine kinase inhibitors, the severity of the rash related strongly to both response and survival. This hypothesis was tested in the EVEREST trial, in which patients with irinotecanrefractory CRC are randomly assigned to treatment with irinotecan plus cetuximab on either a conventional dose-schedule or titrated to a maximal-tolerated rash. By increasing cetuximab doses,a slightly higher skin reaction and response rate could be induced in the experimental arm. On the other hand,important phase III trials will present results in the near future (CRYSTAL and CALGB/SWOG 80405 trial). It remains to be seen if those trials can validate the encouraging data about cetuximab in the first-line treatment.