Insulin resistance and insulin secretory dysfunction are the major metabolic defects in people with type 2 diabetes mellitus. The temporal sequence by which these abnormalities develop and their relative pathophysiologic importance at the various stages of the development of the disease continue to be the objects of considerable debate. In 1982, the National Institutes of Health initiated a comprehensive study of the pathogenesis of type 2 diabetes among the Pima Indians of Arizona, a population with an exceptionally high prevalence of the disease. By the year 2000, insulin sensitivity (two-step hyperinsulinemic glucose clamp) and early insulin secretion (25-g intravenous glucose tolerance test) had been measured in more than 500 Pima Indians with varying degrees of glucose tolerance from normal to impaired to diabetes, many of whom were followed over time and underwent repeated metabolic testing as their glucose tolerance worsened. Cross-sectional, prospective, and longitudinal analyses indicate that both insulin resistance and insulin secretory dysfunction (1) are present in nondiabetic people at high risk for the disease, (2) independently predict worsening of glucose tolerance at each stage of the development of the disease (primary defects), and (3) progressively worsen as people transition from normal glucose tolerance to impaired glucose tolerance to diabetes (secondary defects). These findings have important implications for the primary prevention of type 2 diabetes because they indicate that interventions should begin at an early stage and target both insulin resistance and insulin secretory dysfunction.