Most molecular analyses of head and neck squamous cell carcinoma involve patients who have used tobacco and alcohol. The pathways involved in tumorigenesis in patients lacking these lifestyle risks may be quite different. Research involving rigorous epidemiologic and molecular methods is needed to identify the unique spectra of genetic alterations in subsets of the population. This review considers recent information on the accumulation of genetic changes in the typical head and neck squamous cell carcinoma population and several studies that attempt to analyze subsets of patients categorized by age, gender, and carcinogen exposure. Efforts to identify risk factors in nonsmoking and nondrinking head and neck squamous cell carcinoma patients are evaluated, including studies of family history, human papillomavirus, chromosome fragmentability, microsatellite instability, and carcinogen-metabolizing enzyme genotype.