The glutathione S-transferases (GSTs) catalyze the GSH-dependent detoxification of reactive electrophiles such as genotoxic chemical carcinogens and cytotoxic chemotherapeutic agents. Allelic polymorphism in the GSTs has been used to investigate the hypothesis that GSTs are involved in susceptibility to human cancers. Such studies have resulted in low penetrance, high prevalence associations between cancer risk and GST polymorphisms. By examination of interindividual variation of GST expression it becomes clear that GST genotype alone is not an accurate predictor of GST expression. GST expression is tissue specific and interindividual variation of expression is at least 7-fold in normal tissues. Thus, populations of the same genotype are actually heterogeneous as regards expression. Similarly, polymorphisms are not effective in all tissues and GST induction is not independent of genotype. Mechanistic models for chemical aspects of colorectal cancer and chemotherapy for breast cancer demonstrate some of the ways by which such interactions can be studied and the potential for future studies.