The Endothelin peptides (ET-1, -2, -3) are best known as potent vasoconstrictors. Human ET-1 is synthesized as a pre-pro-polypeptide that is proteolytically cleaved to produce pro-ET-1 and further processed to yield Big ET-1. Big ET-1 is then cleaved by Endothelin-converting enzyme (ECE-1), producing the potent mature form ET-11-21. Alternatively, ET-11-31 can be generated by Chymase mediated cleavage of Big ET-1. ET-1 is predominantly expressed by vascular endothelial cells in response to mechanical stress, various hormones, and pro-inflammatory cytokines. Its production is inhibited by nitric oxide, prostacyclin, and atrial natriuretic peptide (ANP). EDNRA/ETA is the primary receptor responsible for the vasoconstrictor effects of ET-1 and is expressed by blood vessel smooth muscle cells. EDNRB/ETB is additionally present in smooth muscle and the endothelia of blood vessels, kidney, lung, and brain. Endothelins additionally promote cardiac myocyte growth and contraction, smooth muscle cell proliferation, hypothalamic and pituitary hormone secretion, neutrophil adhesion and activation, and angiogenesis. They are involved in multiple pathologies including cancer progression, septic shock, atherosclerosis, heart failure, renal insufficiency, pulmonary hypertension, and cerebral hemorrhage.