Proteinuria is a major long-term clinical consequence of diabetes and hypertension, conditions that lead to progressive loss of functional renal tissue and, ultimately, end-stage renal disease. Proteinuria is also a strong predictor of cardiovascular events. Convincing preclinical and clinical evidence exists that proteinuria and the underlying glomerulosclerosis are reversible processes. This Review outlines the mechanisms involved in the development of glomerulosclerosis-particularly those responsible for podocyte injury-with an emphasis on the potential capacity of endothelin receptor blockade to reverse this process. There is strong evidence that endothelin-1, a peptide with growth-promoting and vasoconstricting properties, has a central role in the pathogenesis of proteinuria and glomerulosclerosis, which is mediated via activation of the ET(A) receptor. Several antiproteinuric drugs, including angiotensin-converting-enzyme inhibitors, angiotensin receptor antagonists, statins and certain calcium channel blockers, inhibit the formation of endothelin-1. Preclinical studies have demonstrated that endothelin receptor antagonists can reverse proteinuric renal disease and glomerulosclerosis, and preliminary studies in humans with renal disease have shown that these drugs have remarkable antiproteinuric effects that are additive to those of standard antiproteinuric therapy. Additional clinical studies are needed.