Publisher Summary This chapter summarizes the growing amount of information on the most potent vasoactive peptide agonist—endothelin. Endothelin is a potent vasoactive peptide mediator that is generated by endothelial cells exposed to a variety of injurious or stimulatory conditions. Most organs and tissues possess receptors for endothelin. Several transmembrane signaling pathways are activated after interaction of endothelin with its receptor. Elevated tissue or plasma levels of endothelin are associated with numerous pathophysiological situations. However, no single disease entity appears to be associated exclusively with endothelin synthesis or response(s). Well-documented responses of endothelin are known in both vascular cells and parenchymal cells. The endothelin is an important signaling molecule in cell–cell interactions between sinusoidal cells and the hepatocytes, as the liver is required to respond to systemic trauma episodes such as sepsis or specifically to hepatic trauma. Hepatic endothelial cells generate this potent peptide mediator whereas Kupffer cells, Ito cells, and hepatocytes possess receptors with which to respond to endothelin.