The incidence of diabetes mellitus was determined in 3137 Pima Indians during periodic examinations that included measurement of weight, height, and glucose tolerance. Incidence was strongly related to preceding obesity, increasing steadily from 0.8 plus or minus 0.8 cases/1000 person-years in subjects with body mass index less than 20 kg/m2 to 72.2 plus or minus 14.5 cases/1000 person-years (rate plus or minus standard error) in those with body mass index greater than or equal to 40 kg/m2, when age-sex adjusted the 1970 US white population. There was little relationship between diabetes prevalence and concurrent obesity, illustrating the importance of longitudinal studies in estimating the effect of obesity on the occurrence of a disease for which weight loss is a manifestation. The association of diabetes incidence with obesity remained within each group when subjects were classified by the diabetic status of their parents, another important risk factor for diabetes. Adjusted for age and obesity, incidence was 2.3 times as high (p = 0.039) in subjects with one diabetic parent and 3.9 times as high (p = 0.0003) in those with two diabetic parents as in those with two nondiabetic parents. In the Pimas, both obesity and diabetes have become more common during this century, perhaps as a result of rapid cultural and dietary changes in a population genetically susceptible to diabetes. Similar increases in obesity and diabetes appear to be occurring in many other parts of the world.