The vascular endothelium is now recognized as an important organ in the non-neural regulation of vascular tone. In particular, it is now well established that endothelial cells release various paracrine factors that relax as well as contract vascular smooth muscle cells. The relaxing factors include endothelium-derived relaxing factor (EDRF), which has been demonstrated to be nitric oxide or a nitric oxide-containing compound, prostacyclin (PGI2) and endothelium-derived hyperpolarizing factor (EDHF). The chemical properties and nature of EDHF are still unknown. Endothelial cells also release vasoconstrictor peptides, the endothelins, which increase smooth muscle Ca2+concentration, resulting in potent vasoconstriction. Since the formation of all these endothelium-derived factors is due to changes in endothelial free Ca2+, the main purpose of the present review is to summarize current knowledge of the underlying molecular mechanisms involved in agonist-induced Ca2+regulation and the mechanisms by which endothelial Ca2+concentrations regulate the formation of endothelium-derived vasoactive factors.