Head and neck squamous cell carcinomas (HNSCC) arise as a consequence of cumulative genetic changes brought about by continued exposure to carcinogens associated with tobacco and alcohol use, influenced by viral agents such as human papillomaviruses, in a background of acquired or heritable genetic susceptibility. The presence of widespread genomic instability in HNSCC, such as cytogenetic aberrations, allelic imbalance/loss of heterozygosity, and microsatellite instability, suggests that there is an imperfection in the host DNA repair machinery. Genomic instability with progressive accumulation of detrimental genetic alterations appears to be dependent upon a circuitous interaction between the environmental genotoxic insults and the host DNA repair machinery, the functional integrity of which is governed by the proper cell cycle control and host DNA repair capacity. Thus, it can be hypothesized that continued exposure to environmental carcinogens (ie, longstanding history of smoking and drinking), loss of proper cell cycle control (eg, inactivation of p53 or p16 tumor suppressor genes or amplification of the proto-oncongene cyclin D1), and impaired DNA repair capacity (both inherited and acquired) are prerequisites in head and neck carcinogenesis.