In patients with squamous cell carcinoma of the head and neck (SCCHN), tumor recurrence, secondary tumors, and comorbidities contribute to therapy failure, and treatment approaches often are limited by their toxicity. With the incorporation of targeted therapies, the number of options available for patients with SCCHN is growing. The epidermal growth factor receptor (EGFR) is involved in the development and progression of SCCHN and is associated with a poor prognosis. The anti-EGFR monoclonal antibody (MoAb) cetuximab is the first targeted therapy to be developed for SCCHN. Recent data confirmed a survival advantage and enhanced locoregional control of SCCHN with cetuximab plus radiotherapy (RT) in patients with locally advanced (LA) SCCHN. Single-agent cetuximab conferred clinical benefits for patients with platinum-refractory metastatic disease, and a recent phase 3 trial demonstrated a survival benefit with cetuximab and standard platinum-based therapy in the front-line treatment of recurrent/metastatic disease. Cetuximab has a toxicity profile milder than that of cytoxic agents and does not exacerbate RT toxicity when it is used in combination. Small-molecule EGFR-tyrosine kinase inhibitors also have shown promise in combination with chemoradiotherapy or as single agents, although they are in earlier stages of developmental. Other targeted approaches (eg, antiangiogenics) are also under investigation. Ongoing clinical trials will further define targeted treatment roles in all stages of SCCHN. Cancer 2008. © 2008 American Cancer Society.