When endothelin-1(ET-1) was discovered it was hailed as the prototypical endothelium-derived contracting factor (EDCF). However, over the years little evidence emerged convincingly demonstrating that the peptide actually contributes to moment-to-moment changes in vascular tone elicited by endothelial cells. This has been attributed to the profound inhibitory effect of nitric oxide (NO) on both the production (by the endothelium) and the action (on vascular smooth muscle) of ET-1. Hence, the peptide is likely to initiate acute changes in vascular diameter only under extreme conditions of endothelial dysfunction when the NO bioavailability is considerably reduced if not absent. The present essay discusses whether or not this concept should be revised, in particular in view of the potent inhibitory effect exerted by calcitonin gene related peptide (CGRP) released from sensorimotor nerves on vasoconstrictor responses to ET-1.