Proteinuria is one of the major risk factors for renal disease progression in patients with chronic nephropathies. Studies in disease models have helped to delineate mechanisms leading to renal structural damage as a result of persistent dysfunction of the glomerular barrier to proteins, even when the primary immune or non-immune insult to the kidney has ceased. From these preclinical studies, a role for endothelin in proteinuric chronic renal diseases has been suggested, thus providing the rationale for novel therapeutic approaches with endothelin receptor antagonists to maximize renoprotection so far achieved with blockade of the renin-angiotensin system by angiotensin-converting enzyme inhibition or angiotensin II receptor antagonism. Trials are needed to explore this potential area of clinical interest.