This review aims to explore the genetic mechanisms involved in the development of squamous cell carcinoma of the head and neck (SCCHN). The epidemiology of SCCHN is complex due to the multiple molecular events that occur and the number of environmental agents to which individuals may have been exposed. It is clear that the major aetiological agents are tobacco and alcohol but it is also becoming apparent that other factors such as an underlying genetic susceptibility may also be important. An inherited predisposition may occur as a consequence of increased mutagen sensitivity, inability to metabolize carcinogens or pro-carcinogens or repair DNA damage. The current advances in understanding of the roles of somatic mutations, viral infection and angiogenesis are discussed. The final part of this review focuses on the way in which molecular changes may be used for prevention, early diagnosis and treatment of SCCHN.