In the past decade, research has advanced our understanding how endothelin contributes to proteinuria and glomerulosclerosis. Data from pre-clinical and clinical studies now provide evidence that proteinuric diseases such as focal segmental glomerulosclerosis and diabetic nephropathy as well as hypertension nephropathy are sensitive to treatment with endothelin receptor antagonists (ERAs). Like blockade of the renin-angiotensin system, ERA treatment-under certain conditions-may even cause disease regression, effects that could be achieved on top of renin-angiotensin-aldosterone system blockade, suggesting independent therapeutic mechanisms by which ERAs convey nephroprotection. Beneficial effects of ERAs on podocyte function, which is essential to maintain the glomerular filtration barrier, have been identified as one of the key mechanisms by which inhibition of the endothelin ETA receptor ameliorates renal structure and function. In this article, we will review pre-clinical studies demonstrating a causal role for endothelin in proteinuric chronic kidney disease (with a particular focus on functional and structural integrity of podocytes in vitro and in vivo). We will also review the evidence suggesting a therapeutic benefit of ERA treatment on the functional integrity of podocytes in humans.