Genetic and environmental determinants play critical roles in insulin resistance and beta-cell function. A model of the complex feedback system for maintenance of glucose tolerance has been developed that reflects the constraint of glycemia within narrow physiologic limits. The "glucose homeostasis" model is described by insulin sensitivity, glucose effectiveness, acute insulin response to glucose, and disposition index (DI). Relatively little is known about the genetic basis of glucose homeostasis phenotypes or their relationship to risk of diabetes and atherosclerotic cardiovascular disease. There is increasing evidence that variation in glucose homeostasis reflects genetic control better than that of commonly used surrogate measures (fasting glucose or fasting insulin). Further, recent linkage scans have identified regions in the human genome that may contain loci that contribute to variation in glucose homeostasis phenotypes. Thus, the prospects are encouraging for positional cloning of genes contributing to glucose homeostasis and providing insight into the nature of the metabolic syndrome and diabetes. Ultimately, knowledge of the genetic basis of glucose homeostasis will facilitate the development of more directed therapies for prevention and treatment of diabetes and other diseases associated with disordered glucose metabolism.