Alcohol, particularly when associated with tobacco use, has been recognized as an important risk factor for mouth cancer for almost 50 years. Together, they are associated with approximately 75% of upper aerodigestive tract cancers. However, intake of alcohol remains high in many countries. The rising incidence of oral cancer has prompted a revaluation of the role of alcohol (both alone and in partnership with other etiologic agents). In this article, the potential role of alcohol in the development of oral cancer is reviewed. In particular, the effect of alcohol on cellular structure and function is considered by reference to histologic and exfoliative cytologic studies of the oral epithelia. Alcohol may influence the proliferative cells by both intracellular (e.g., endocytosis) and intercellular (permeability) pathways. The carcinogenic exposure of the proliferating stem cells in the basal layer may be regulated through these pathways. Individual variation might help explain why oral cancer arises in some, but not in most, people who smoke and consume excess alcohol. Despite this finding, alcohol is strongly associated with the development of oral cancer and other upper aerodigestive tract cancers. Efforts to reduce this burden on the individual and society must be directed toward patient and professional education and research regarding (genetic) susceptibility.