The Pima Indians of Arizona have the highest reported prevalence and incidence of non-insulin dependent diabetes mellitus (NIDDM) of any population in the world. Since 1982, we have been studying a subset of this population to determine the metabolic characteristics that predispose individuals in the population to develop the disease. Approximately 300 subjects were entered into the study and are followed yearly. Subjects are admitted to the clinical research ward and undergo several studies including underwater weighing, oral glucose tolerance test, intravenous glucose tolerance test, standard mixed meal test, and a two-step hyperinsulinemic, euglycemic clamp to measure insulin action in vivo. This past decade approximately 40 subjects have developed NIDDM during the course of this study. Analyses of the data collected to date indicate that insulin resistance is a major risk factor for the development of NIDDM, independent of the risk associated with being obese. In addition, among individuals who are insulin resistant a lower acute insulin response is an additional risk factor. However, those individuals with a low acute insulin response have acute insulin responses that are the same or higher as a matched group of Caucasian individuals. These data suggest that insulin resistance is the major risk factor for the development of NIDDM in the Pima population and is probably the explanation for the greater prevalence of the disease in this racial group. Among insulin resistant persons, a low acute insulin response is an additional risk factor for the development of NIDDM. Both insulin resistance and a low acute insulin response appear to cluster in families and both have a frequency distribution that is not fit by a unimodal distribution. These data suggest there may be genetic factors that contribute to insulin resistance and lower acute insulin responses in this population.