Approaches to the treatment of locally advanced and recurrent and/or metastatic squamous cell carcinoma of the head and neck (SCCHN) have been limited by their toxicity. Effective, better tolerated approaches are urgently required. Cetuximab is an immunoglobulin G(1) monoclonal antibody that specifically targets the epidermal growth factor receptor (EGFR), which is commonly expressed in a number of solid tumors, including SCCHN, where it is associated with poor prognosis. Cetuximab is approved in 56 countries for use in the treatment of EGFR-expressing metastatic colorectal cancer that has progressed on irinotecan-containing therapy and has recently received approval in Europe and the USA for use in the treatment of SCCHN. A randomized Phase III study has demonstrated that cetuximab plus radiotherapy can significantly improve locoregional control and prolong overall survival compared with radiotherapy alone. Cetuximab has also been confirmed to be effective as monotherapy in recurrent and/or metastatic SCCHN that has progressed on platinum-containing therapy. Clinical studies have demonstrated that cetuximab is well tolerated and does not significantly increase the side effects associated with radiotherapy or chemotherapy. This article presents the rationale for EGFR inhibition in the management of head and neck cancers, and the preclinical and clinical evidence for the use of cetuximab in the treatment of SCCHN.