The suggestion that the peptide endothelin (ET)-1 contributes to the development of hypertension was clearly evident from the first in vivo characterization of ET-1. In the ganglion-blocked rat, Yanagisawa first reported that a 1 nmol/kg intravenous injection of ET-1 produced a transient decrease in blood pressure lasting <30 seconds followed by a sustained hypertension.1 These findings stimulated an incredible response in new research especially within the pharmaceutical industry including some efforts to target the ET system for the treatment of hypertension. Two receptor subtypes, ETA and ETB, mediate the opposing actions of ET-1. We now know that the slow and sustained hypertensive response is mediated primarily by ETA receptor activation on vascular smooth muscle. Importantly, the hypotension is attributable to endothelial-dependent relaxation mediated by the ETB receptor. The purpose of this review is to highlight some of the more important aspects of the ET system as it relates to the physiological and pathophysiological role in the regulation of blood pressure and development of hypertension. It should be noted that the ETA and ETB receptor systems are important in craniofacial and enteric nerve development, respectively, so the reader is referred elsewhere for more details on these topics.2,3 There are a several unique aspects of the ET system that are worth mentioning because of their unique nature compared with more classical peptide/G-protein–linked receptor systems. Probably the most unusual aspect of this system that has made it difficult to study through the years is the irreversible binding of the endogenous ligand to the receptor.4 This binding is believed to account in large measure for the prolonged vasoconstrictor actions of ET-1 mediated by the ETA receptor. Importantly, the same ligand-binding behavior exists for the ETB receptor such that loss of …