Endothelin is a naturally occurring peptide with potent vasoconstrictive and inotropic actions. Its cardiac actions involve binding to endothelin receptors coupled to pertussis sensitive guanine-nucleotide regulatory proteins and initiating a receptor-second messenger pathway by activating phospholipase C and phosphatidyl-inositol hydrolysis. Endothelin appears to enhance myocardial contractility mainly through sensitizing the myofilaments to Ca2+ by increased levels of inositol triphosphate and diacylglycerol as well as intracellular alkalization due to enhanced Na+/H+ antiporter activity. It also appears to increase intracellular Ca2+ concentrations in the presence of an agonist such as nucleotide-triphosphate by prolonging action potential duration to permit an increased period for Ca2+ entry and possibly activating sarcolemmal L-type calcium channels. Endothelin plays a significant role in the basal regulation of cardiac functions, and its mechanisms thereof are beginning to be understood. In failing and ischemic hearts, endothelin also exerts effects which are notably different from those seen in the normal heart. These pathophysiologic roles of endothelin as well as their interactions with other vasoactive and cardioactive humoral agents will need to be explored further, particularly with the newly discovered endothelin receptor antagonists.