Diabetes affects American Indians disproportionately compared with other racial/ethnic groups in the United States and is almost exclusively type 2 diabetes. Much of our knowledge about diabetes in American Indians comes from studies in a few tribes. The most extensively studied American Indians are the Pima Indians from the Gila River Indian Community in Arizona, who participated in a longitudinal study of diabetes and its complications between 1965 and 2007. They have one of the highest reported incidence and prevalence of type 2 diabetes in the world, and kidney disease attributable to diabetes is a major cause of morbidity and mortality. In this article, we examine the course, determinants, and trends of diabetic kidney disease in American Indians, with special emphasis on studies conducted in the Pima Indians. We also review therapeutic strategies for managing diabetic kidney disease.