Today diabetic nephropathy is the leading course of end-stage renal disease; the incidence and prevalence of diabetic renal disease is still continuing to increase, particularly in the Western world. Despite improvements in diagnosis and treatment of diabetic nephropathy, only partial renal protection is reached with the current standard therapy regiments, including angiotensin-converting enzyme inhibitors and/or angiotensin receptor blockers. Against this background, it is of particular importance to learn more about the pathogenesis of diabetic nephropathy and to find new therapeutic approaches which alone or in combination with standard therapy have the potential to prevent or delay the progression of diabetic nephropathy, thus improving kidney and patient survival. Among others, endothelin (ET) receptor blockers have emerged as a potential therapeutic option that operates on the basis of physiological and pathophysiological effects of endothelin. Of note, the ET system was shown to be involved in hypertension and kidney disease, particularly proteinuric nephropathies, and there is good experimental data indicating a specific role of ET in the pathogenesis and progression of diabetic nephropathy. ET receptor blockers have been shown to be nephroprotective in animal models of type 1 and type 2 diabetes mellitus with the effects partly independent of blood pressure lowering. In patients with hypertension and diabetic nephropathies, the data is controversial and depends on the stage of the disease and the drug used. It was only recently that a large international clinical study (ASCEND) provided evidence for beneficial effects of ET antagonist treatment, i.e. reduction in proteinuria. Due to the premature termination of the study, however, hard endpoints like death could no longer be assessed. Another very recent randomized, double-blind, placebo-controlled trial of subjects with diabetic nephropathy also provided evidence for a specific antiproteinuric effect of the ET receptor antagonist atrasentan on top of an already existing blockade of the renin-angiotensin system. Thus, it appears currently of great scientific and clinical interest to shed some light on the role of the ET system and its blockade in diabetic nephropathy. Copyright © 2011 S. Karger AG, Basel.