Three etiologies of renal disease account for more than 80% of Medicare-supported (U.S. Federal Government sponsored) end-stage renal disease (ESRD) cases: diabetes mellitus, hypertension and chronic glomerulonephritis. Surprisingly, despite improvements in medical care, their incidence is increasing rapidly in many parts of the world. With the exception of autosomal dominant adult polycystic kidney disease, the DNA polymorphisms causing progressive renal failure in individuals with common diseases have not yet been identified. Although hypertension and diabetes mellitus are associated with ESRD, the majority of patients with these disorders never develop nephropathy. There is abundant evidence that both inherited factors and the environment affect the development of ESRD. Predisposition to nephropathy may be inherited independently from the environmental and hereditary components that produce the associated systemic disease. This review examines the evidence that ESRD results, in part, from inherited factors. It discusses the racially variable risk of renal disease, the familial clustering of ESRD and molecular genetic data in animals and humans with renal failure.