Squamous cell carcinoma of the head and neck (SCCHN) is a group of cancers of epithelial origin that may provide an ideal model for the study of gene-environment interaction. SCCHN includes squamous cell carcinomas of the oral cavity, pharynx, and larynx. Approximately 90% of the attributable risk for oral cancer and 80% of the attributable risk for larynx cancer results from tobacco use. Tobacco smoking has been demonstrated to increase the risk of SCCHN in a dose-response fashion. Polymorphisms of carcinogen-metabolizing enzymes, known to be involved in metabolism of carcinogens found in tobacco smoke, are relatively common in most populations. This paper provides a concise review of the 24 published studies that evaluated the risk of SCCHN in relation to two deletion polymorphisms of the glutathione S-transferase family: GSTM1 and GSTT1. Patterns of risk based on the site of the tumor and on nationality are presented, as are some methodological weaknesses of the studies. The results of these studies are inconsistent, with some reporting weak-to-moderate associations and others finding no elevation in risk for the main effect of the gene. Few studies have directly evaluated the interaction with tobacco. Well-designed, population-based studies of adequate size are needed.