The prototypic head and neck squamous cell carcinoma (HNSCC) arises from the mucosal lining of the upper aerodigestive tract, demonstrates squamous differentiation microscopically, involves older men with a long history of cigarette smoking and alcohol consumption, and is treated by multimodality therapy. HNSCC has long been regarded as a uniform disease process requiring a methodical and unwavering therapeutic approach. Divergence in epidemiologic trends among HNSCCs arising from different anatomic sites has introduced a view that, morphologic repetition aside, head and neck cancers form a heterogeneous group. This view has been supported at the molecular genetic level. A more complete understanding of the molecular genetics of head and neck cancer is providing new insights into long-held but poorly comprehended concepts such as field cancerization and is introducing various biomarkers with potential application for diagnosing, staging, monitoring, and prognosticating HNSCC.