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ET\u20101 is synthesized by ET\u2010converting enzymes (ECE), chymases (CMAs), and non\u2010ECE metalloproteases through a process regulated in an autocrine fashion in vascular and nonvascular cells. ET\u20101 acts through the activation of G<jats:sub>i<\/jats:sub>protein\u2013coupled receptors. ET<jats:sub>A<\/jats:sub>receptors mediate vasoconstriction and cell proliferation, whereas ET<jats:sub>B<\/jats:sub>receptors are important for aldosterone secretion, endothelial cell (EC) migration, the release of nitric oxide (NO) and prostacyclin, the clearance of ET\u20101, and the inhibition of<jats:italic>ECE\u20101<\/jats:italic>. ET is activated in scleroderma, hypertension, atherosclerosis, restenosis, heart failure, idiopathic cardiomyopathy, and renal failure. Tissue concentrations more reliably reflect the activation of the ET system because of the predominantly abluminal secretion of the peptide. Experimental studies and clinical trials have demonstrated that ET\u20101 plays a major role in normal cardiovascular homeostasis and in the functional and structural changes observed in arterial and pulmonary hypertension, glomerulosclerosis, atherosclerosis, and heart failure. Accordingly, ET antagonists are promising new agents in the treatment of cardiovascular diseases. Single nucleotide polymorphisms (SNPs) of the genes of<jats:italic>preproET\u20101<\/jats:italic>,<jats:italic>ECE\u20101<\/jats:italic>, CMA, ET<jats:sub>A<\/jats:sub>and ET<jats:sub>B<\/jats:sub>receptors have been identified and can be important for their functional regulation. However, for most of them the association with disease conditions and the evidence for a functional role remain controversial. 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