The prognosis of metastatic colorectal cancer (mCRC) remains poor despite the advances made in recent years with new therapeutic agents, surgical procedures, and diagnostic methods. New treatments directed toward molecular targets have emerged and are being developed to improve these results, but there is a need to optimize and define the best use of these new approaches. Cetuximab is a chimeric monoclonal antibody that binds to the epidermal growth factor receptor and thereby inhibits cell proliferation, metastasis, and angiogenesis. Preclinical studies indicate that cetuximab induces synergistic antitumor activity when combined with chemotherapy or radiation. In pretreated patients with mCRC, cetuximab might restore sensitivity toward irinotecan and has therefore been registered for the treatment of patients with mCRC refractory to irinotecan. Moreover, cetuximab seems to add substantial benefit to standard oxaliplatin- and irinotecan-based combinations, resulting in high response rates in the first-line setting. Recent preclinical and clinical data have optimized cetuximab therapy. New targeted therapy combinations and the identification of biomarkers associated with disease control in patients treated with cetuximab are changing the current management of mCRC. Also, preliminary data suggest that cetuximab can be administered in a more convenient 2-week schedule in combination with standard chemotherapy.