Over the past few decades, the disease burden among American Indians and Alaska Natives (Al/AN) has shifted from acute infectious diseases to chronic illnesses, particularly type 2 diabetes and its complications. AI/ANs experience high rates of end-stage renal disease (ESRD), mainly driven by the increase in diabetes. The prevalence of ESRD is 3.5 times greater than that in white Americans. The burden of ESRD has become a community-wide problem among many tribes, and significant efforts have gone into establishing dialysis services on reservations. Reservation-based dialysis services have improved the access of patients to renal replacement therapy, but enormous barriers to improving care remain. These include: the rural and frequently isolated locations that make traveling to facilities difficult owing to distance and road conditions; high rates of poverty; difficulty in recruiting and retaining staff in outlying areas; language and cultural differences; and the high numbers of patients with diabetes and extra-renal diabetic complications. Disparities exist in access to kidney transplantation, with AI/ANs waiting longer for organs than their white counterparts. However, once transplanted, they have comparable survival rates to white Americans. An aggressive approach to intervention, which includes prevention and optimal therapy, is required to slow the growth of ESRD amongst AI/ANs.