Since the original discovery of endothelin (ET) by Yanagisawa et al in 1988,1 the scientific interest in this area of research has grown exponentially. It was originally hypothesized that ET interacts with two subtypes of receptors to mediate its biological functions and subsequent cloning of two ET receptors confirmed the original hypothesis. As with any receptor, especially seven transmembrane G protein-coupled receptors, identification of receptor subtypes has always been aided by antagonists, and ET receptors are not an exception to this. According to the original definition, the ET receptors which mediated vasoconstriction were classified as ETA and those which mediated vasodilation were classified as ETB receptors. This classification was based on the potency of various agonists such as ET-1, ET-2, ET-3, and S6c.2–5 In addition, radiolabeled ET-1 and ET-3 were also used to classify the two subtypes of ET receptors in various tissues. BQ-123, the very first ET receptor antagonist (selective for ETA receptors) identified, also was very useful in this classification scheme of the subtypes of ET receptors.6 However, just like many other seven transmembrane G protein-coupled receptors, the two receptor models appeared insufficient to explain all the biological and pharmacological data obtained for ET peptides. This would indicate that there may be additional subtypes of ET receptors. This became clear with the development of very potent nonpeptide antagonists as well as peptide agonists such as IRL-1620, 4-Ala ET-1, etc. As mentioned above, according to the original classification, ET receptors that mediated vasoconstriction were termed ETA and those that mediated vasodilation were termed ETB receptors.