Head and neck cancer is a challenging disease that is expected to account for greater than 500,000 new cases worldwide in 2008. Toxicity has impeded advances in chemotherapy and radiation for head and neck cancer, and the prognosis for patients with recurrent and/or metastatic disease remains poor. Over the past decade, clinical research in head and neck cancer has focused on improving the efficacy of current multimodal approaches by targeting cellular pathways associated with carcinogenesis. Blocking the epidermal growth factor receptor (EGFR) and the vascular endothelial growth factor receptor (VEGFR) have emerged as primary strategies that account for the success of current targeted therapies in cancer. Recent studies with cetuximab, a monoclonal antibody inhibitor of the EGFR, have demonstrated survival benefits across the range of treatment settings in advanced head and neck cancer, and it is the only targeted therapy approved for use in this malignancy. In this review, the authors present the current development status of targeted therapies, focusing on those that have potential to impact the management of head and neck cancer in the near-term future. Trials are ongoing in all stages of disease and with a variety of modalities and agents, and those trials should provide critical insight into the best way to use these agents to improve patient outcomes.