Endothelin (ET)-1 is a powerful mitogen and vasoconstrictor that contributes to cardiovascular and renal pathologies. In the kidney, ET causes vasoconstriction, sodium retention, mesangial cell inflammation and proliferation, hypertrophy of glomerular capillaries, and podocyte injury. The latter, due to destruction of the glomerular filtration barrier, is a key factor for renal protein loss. Experimental and recent clinical studies suggest that orally active drugs inhibiting ET_A receptors are capable of not only inhibiting the progression, but also reversing glomerulosclerosis-related renal injury. Clinical studies using ET receptor antagonists (ERAs) have found regression of proteinuria which serves as a functional indicator of glomerular filtration barrier injury. The effects of ERA therapy can be observed in the presence of inhibition of the renin-angiotensin system, suggesting arenin-angiotensin system-independent therapeutic effect of ERAs. Thus, ET blockade is not an ‘add-on’ treatment, but represents an independent therapeutic principle. This article will discuss the underlying mechanisms of the antiproteinuric effects of ET antagonists, and summarize recent clinical trials in the field and the therapeutic potential of the ERA class of drugs for renal medicine.