After the ingestion of glucose, insulin secretion by the pancreas is stimulated, and the combination of hyperinsulinemia plus hyperglycemia must effectively promote glucose uptake by splanchnic (liver and gut) and peripheral tissues (primarily muscle) and suppress hepatic glucose production (HGP). From this brief overview, it is obvious that defects at the level of the (3-cell, muscle, or liver can lead to the development of glucose intolerance or overt diabetes mellitus. In this article, the concept is developed that there are two primary defects responsible for the pathogenesis of non-insulin-dependent diabetes mellitus (NIDDM). In some NIDDM patients the primary defect starts at the level of the (3-cell and manifests itself as an impairment in insulin secretion; these individuals are represented by the lean diabetic patient. In other NIDDM patients the primary defect starts as an impairment in tissue (muscle and liver) sensitivity to insulin; these individuals are represented by the obese diabetic. However, whichever defect—diminished insulin secretion or insulin resistance—initiates the development of NIDDM, it will subsequently lead to the emergence of the second abnormality. In fact, both defects must be present simultaneously before moderate to severe glucose intolerance ensues. Although deranged hepatic glucose metabolism plays an important role in maintaining the diabetic state once it has become firmly established, the liver probably does not play a major role in the early development of fasting hyperglycemia in NIDDM patients.