American Indians and Alaska Natives (AI/AN) experience high rates of chronic kidney disease. Several studies have demonstrated increased rates of early kidney disease among AI/AN, both in diabetics and non-diabetics. Among some tribes of the American Southwest, high rates of mesangiopathic glomerulonephritis have been documented. The epidemic of diabetes among AI/AN, which began in the middle of the 20th century, appears to be driving the increase in end-stage renal disease (ESRD). At the end of 1999, AI/AN had a national prevalence rate of treated ESRD that was 3.5 times greater than that of white Americans. There is significant regional variation as well as differences among the approximately 550 tribes that make up the American Indian community, with some tribes experiencing ESRD rates over twenty times the rate of whites. Although graft survival is excellent, AI/AN ESRD patients are less likely than whites to be placed on the transplant waiting list, and those listed wait longer for a transplant. Despite socioeconomic barriers and high rates of co-morbid illness, survival among AI/AN ESRD patients is better than among whites. The burden of kidney disease, particularly the multigenerational occurrence in some families, is perceived as a major threat to the well-being of native communities. There is a sense of urgency among tribal leaders to address this epidemic, and research that may decrease its burden is likely to be welcomed.