It is clear from descriptive and migration studies that most cancer is environmental in origin. Descriptive, case-control and cohort studies have provided the foundation for our understanding of the environmental component of cancer etiology as well as most major causes of morbidity and mortality. We propose that the same epidemiologic methods that have provided fundamental insight into the etiology of cancer in the general population are optimally suited to study the impact of relatively common polymorphisms on chronic disease incidence. In this article, we describe the role of case-control studies in assessing the effects of genes in disease. Some of the advantages and disadvantages of the case-control design, particularly as an alternative to case-control studies nested in a cohort in the context of the study of complex disease, are described.