Approximately 50,000 new cases of head and neck squamous cell carcinoma (HNSCC) will be diagnosed in the United States in 2009. Although the gradual decline in smoking rates in the United States is a highly favorable trend, the future global HNSCC incidence will likely reflect the increased marketing and penetration of tobacco products across several of our most populous countries. Although modern surgery, radiation, and conventional chemotherapy strategies for HNSCC continue to provide gradual improvement in outcome, the first molecular targeting approach to show a survival advantage for HNSCC patients has recently emerged in the context of epidermal growth factor receptor biology. The scientific background and current challenges accompanying this recent advance are described in this article as are several additional promising molecular targets for HNSCC. There is cautious anticipation that the logical advancement of molecular targeting agents in conjunction with radiation may afford increased cure rates and diminished normal tissue toxicity profiles for HNSCC patients over the years to come.