Purpose of reviewThe two leading causes of end-stage renal disease in the United States are diabetes mellitus and hypertensive nephrosclerosis, accounting for over two-thirds of all cases. In many patients both diseases are associated with small- and large-vessel disease, commonly attributed to hypertension or accelerated atherosclerosis. Recent investigations, however, have suggested that renal large-vessel and microvascular disease may be independent contributors to progressive kidney failure.Recent findingsAlthough genes have not been definitely linked to renal vascular disease, population- and family-based epidemiology of kidney disease, segregation analysis of Pima and Caucasian families in which diabetic nephropathy is clustered, and the positional cloning of genes responsible for rare, familial glomerulosclerosis syndromes support the hypothesis that genes regulate the pathogenesis of renal disease. This review highlights developments in our current understanding of vasculopathy and its role in renal disease, and it summarizes evidence suggesting that genetic determinants for the vascular phenotype are associated with common causes of chronic renal failure.SummaryWith the application of genomics and proteomics methodologies to drug discovery, the identification of renal susceptibility genes should identify new mechanisms of progressive renal disease pathogenesis and generate novel target molecules for the treatment of kidney disease.