Head and neck squamous cell carcinoma (HNSCC) include squamous cell carcinomas of the oral cavity, pharynx, and larynx. Epidemiologic data suggest that the etiology and pathogenesis of HNSCC are influenced by environmental and lifestyle-related factors, such as tobacco use, ethanol consumption, papilloma virus infection, dietary factors and exposure to toxic substances. DNA repair systems and carcinogen-metabolizing enzymes can increase the risk for HNSCC but no definite causal mechanism has been demonstrated. There are several well-characterized entities that are associated with risk and prognosis of head and neck cancer, including Lynch-II syndrome, Bloom syndrome, Fanconi's anemia, xeroderma pigmentosum, ataxia telangiectasia, and Li-Fraumeni syndrome. This review aims to present the current status in our understanding of HNSCC and highlight controversies relating to the role of several factors in the genesis of the cancer.