The comprehensive longitudinal studies of diabetes conducted in the Pima Indians of Arizona over the last 30 years indicate that both genetic and environmental factors play a critical role in the pathogenesis of the disease. Pre- and postnatal exposures as well as diet and physical activity in adulthood markedly affect risk of developing NIDDM in this population. In addition, the high prevalence of diabetes in the Pimas relative to other populations and the familiality of the disease and its precursors, strongly suggest a substantial genetic basis. Interactions between genes and the environment are obviously important in the pathogenesis of NIDDM, but it remains unclear exactly how these interactions occur and how to adequately account for these effects when searching for genes contributing to diabetes. The realization that gene-environment interactions are significant, and may be the dominant mechanism increasing susceptibility to NIDDM, should encourage further investigations. Future progress in studying the genetics of NIDDM and other complex diseases will come not only from technical advances currently in development, but also from advances in understanding the pathophysiology of the disease and the role of gene-environment interactions, and a renewed emphasis on careful clinical characterization of subjects participating in these studies.