Pima Indians have the highest prevalence of non-insulin-dependent diabetes mellitus reported in the world, reaching 70% in the 55-64 year age-group. Although obesity is also quite prevalent in this population, it cannot in itself be held responsible for the high frequency of the disease. Profound changes in the way of life of the Pima Indians during the past century have been associated with the emergence of diabetes. A genetic susceptibility in this population probably explains why diabetes became an "epidemic". Compared to Caucasians with similar degrees of obesity and glucose tolerance, Pima Indians are insulin-resistant. This characteristic, which is a strong predictor of diabetes, seems to be genetically determined in this population, and an active search for the gene(s) involved has started. Surprisingly, for an insulin-resistant population, cardiovascular mortality is low in Pima Indians. An understanding of the similarities and differences between diabetic Caucasians and Pima Indians is one means of advancing our knowledge of non-insulin-dependent diabetes mellitus and insulin resistance.