NIDDM in Pima Indians is characterized by obesity, abnormal insulin secretion, insulin resistance, and excess hepatic glucose output. Cross-sectional studies, and, as yet incomplete longitudinal studies of nondiabetic and diabetic Pima Indians suggest that the natural history of the disease begins with insulin resistance and, subsequently, when insulin secretion fails, increasing hepatic glucose output occurs, resulting in increasing fasting hyperglycemia. The insulin resistance that precedes the development of fasting hyperglycemia is not due solely to obesity. Insulin resistance aggregates in families and the trimodel frequency distribution of insulin action in vivo suggests it may have genetic determinants.