Much remains to be learned about the best ways to integrate molecular-targeted therapies into the chemotherapeutic armamentarium. The epidermal growth factor receptor inhibitor cetuximab has been extensively evaluated in patients with chemotherapy-resistant metastatic colorectal cancer. In patients with irinotecan-refractory or irinotecan/oxaliplatin-refractory disease, single-agent cetuximab has produced a partial response in 9% to 11.6% of patients and stable disease in 21.6% to 36.8%. In irinotecan-resistant disease, the combination of cetuximab and irinotecan has resulted in partial responses in 17% to 22.9% of patients and stable disease in 31% to 32.6%. The degree of epidermal growth factor receptor expression has not been predictive of treatment response; severity of a characteristic acneiform rash does appear to be predictive of response. Ongoing trials in colorectal cancer are examining the combination of cetuximab and bevacizumab with or without irinotecan in irinotecan-refractory disease, irinotecan with or without cetuximab in oxaliplatin-refractory disease, and FOLFOX4 with or without cetuximab in patients receiving first-line irinotecan treatment.