In the past decade the median overall survival of patients with metastatic colorectal cancer has increased from 12 to more than 20 months, mostly due to the new chemotherapeutic agents, irinotecan and oxaliplatin. Most recently, targeted therapies, that inhibit specific cancer pathways and molecules, have shown promising results in the treatment of patients with metastatic colorectal cancer and other solid tumors. One of the most studied targets for anticancer therapy is the epidermal growth factor receptor (EGFR), which is overexpressed in a variety of malignancies. Cetuximab, an anti-EGFR chimeric monoclonal antibody, has shown clinically meaningful antitumor activity in patients with metastatic colorectal cancer in several clinical trials. Efforts of physicians and researchers are currently directed towards the identification of predictive factors (clinical or molecular) of clinical outcome, with the aim of both optimizing the therapeutic index and dealing with increasing costs of these new compounds.