Sickle cell disease (SCD) affects the kidney by acute mechanisms, as a form of the sickle crisis, and insidiously with renal medullary/papillary necrosis, with resulting tubular defects. Glomerular hyperperfusion and hypertrophy results in a chronic sickle cell nephropathy that results in a significant morbidity in the progression to end-stage kidney disease. Kidney transplantation offers a major advantage to survival, and should be coupled with efforts toward prevention of recurrent disease.