Endothelin (ET)-1, an endothelium-derived vasoactive polypeptide encoded in the human genome, is the most potent vasoconstrictor identified to date. In addition to its acute role in modulating vascular smooth muscle tone, ET-1 also plays a critical role in the long-term control of cellular growth within the vasculature and thus, modulates the chronic remodeling of the vascular tree. In order to produce such a diverse range of biological responses, this peptide is able to activate numerous distinct effector systems including phospholipase C, phospholipase D, phospholipase A2, adenylate and guanylate cyclases and numerous cytosolic/nuclear protein kinases. These actions, mediated via an interaction with two major subtypes of cell surface seven-transmembrane receptors (ET(A) and ET(B)), are coupled to their effector systems by several distinct types of guanine nucleotide regulatory proteins (both inhibitory and stimulatory G proteins). This review describes such intercations and how distinct pharmacological agents have been used to identify the diverse signaling mechanisms utilized by the ET isopeptides.