Head and neck squamous cell carcinoma (HNSCC) survival remains poor despite continuing efforts toward prevention, early detection, and improved treatment modalities. In part, this is thought to be due to a relative lack of molecular targeted therapeutic strategies beyond general mitosis inhibition, which sets a limit to what modern head and neck surgery can accomplish for advanced disease. The past 30 years have produced a large quantity of data, leading to a better understanding of HNSCC carcinogenesis and novel therapeutic agents, such as epidermal growth factor receptor blockers. This article reviews literature on the current understanding of molecular HNSCC carcinogenesis, and highlights the most promising therapeutic approaches.