The endothelin system consists of two G-protein-coupled receptors, three peptide ligands, and two activating peptidases. Its pharmacological complexity is reflected by the diverse expression pattern of endothelin system components, which have a variety of physiological and pathophysiological roles. In the vessels, the endothelin system has a basal vasoconstricting role and participates in the development of diseases such as hypertension, atherosclerosis, and vasospasm after subarachnoid hemorrhage. In the heart, the endothelin system affects inotropy and chronotropy, and it mediates cardiac hypertrophy and remodeling in congestive heart failure. In the lungs, the endothelin system regulates the tone of airways and blood vessels, and it is involved in the development of pulmonary hypertension. In the kidney, it controls water and sodium excretion and acid-base balance, and it participates in acute and chronic renal failure. In the brain, the endothelin system modulates cardiorespiratory centers and the release of hormones. More advanced functional analysis of the endothelin system awaits not only additional pharmacological studies using highly specific endothelin antagonists but also the generation of genetically altered rodent models with conditional loss-of-function and gain-of-function manipulations.