Endothelin (ET) is a potent vasoconstrictor associated with various cardiovascular diseases. ET mediates its effects through ET receptors on vascular smooth muscle cells as well as on the vascular endothelium. Furthermore, a neurotransmitter role for ET has been suggested on the basis of experimental and human in vivo studies. ET antagonists are potent tools for studying the effects of ET and its receptors. They have been widely used in vitro and in experimental models of cardiovascular disease, where ET levels are elevated and reactivity to ET is altered. Promising clinical trials in hypertension, coronary artery disease, and congestive heart failure are discussed in this review. Different forms of renal failure are associated with markedly increased ET levels, and ET antagonists experimentally improve renal function in these models. Extrapolating from experimental and first clinical experience, ET antagonists could be useful in the treatment of hypertension, coronary artery disease, congestive heart failure, and renal failure, especially in combination with other drugs, ie, angiotensin converting enzyme inhibitors. The inhibition of ET-induced stimulation of nociception allows for speculation that ET antagonists might even have analgesic properties.