Endothelin is tightly involved in the regulation of vascular and renal function in health and in disease. In a variety of animal models of kidney disease, endothelin promotes renal injury through effects on inflammation and fibrosis. Furthermore, experimental data strongly suggest that blocking the actions of endothelin should be beneficial in patients with chronic kidney disease. However, despite encouraging pre-clinical and clinical evidence, endothelin antagonists are not yet an established treatment option in patients with chronic kidney disease. This article reviews key physiological and pathophysiological aspects of the endothelin system in the vasculature and the kidney, as well as results of pre-clinical and clinical studies on the use of endothelin antagonists in chronic kidney disease. We will also provide an outlook on the future of endothelin antagonism in this area, and issues to be resolved before endothelin antagonists are to become a reality for patients with chronic kidney disease.