The epidermal growth factor receptor (EGFR) is frequently overexpressed in non-small cell lung cancer (NSCLC). EGFR activation results in phosphorylation of several downstream intracellular substrates involved in cell proliferation, angiogenesis, and inhibition of apoptosis. Cetuximab (C225, Erbitux), a monoclonal antibody directed against ligand binding in the extracellular domain of EGFR, inhibits tumor growth and is synergistic with chemotherapy and radiation. Cetuximab has been studied in combination with chemotherapy in previously untreated metastatic NSCLC. The response rates in preliminary reports range from 29% to 53%. In patients with refractory/recurrent NSCLC, the combination of docetaxel and cetuximab resulted in a promising response rate of 28%, higher than the typical response rates seen with docetaxel monotherapy in this setting. Addition of cetuximab to chemotherapy is generally well tolerated. Molecular mechanisms predicting response to cetuximab therapy are currently not well understood. Studies are ongoing to assess the single-agent activity of cetuximab in metastatic NSCLC.