In normal animals, the extracellular concentration of glucose is maintained within a very narrow range by the matching of glucose flux into and out of the extracellular space through the tightly coordinated secretion of insulin and glucagon. Functional alterations in beta-cells, liver, or skeletal muscle and adipose tissue may disrupt glucose homeostasis and lead to the development of non-insulin-dependent diabetes mellitus (type 2 diabetes). This review outlines the contribution of these organs and tissues to the control of glucose homeostasis. We discuss new insights obtained through studies of transgenic mice that overexpress or show decreased expression of putative key genes in the regulation of pancreatic beta-cell function, in the control of hepatic glucose uptake and output, and in the regulation of glucose uptake and utilization by skeletal muscle and adipose tissue.