There is now a considerable evidence that indicates that there is non-NO/prostanoid mediated vasodilation/hyperpolarization mechanism in a variety of blood vessels from different species. It is argued that a factor, EDHF, is responsible for mediating these cellular events and, like NO, EDHF is synthesized and released, in a Ca(2+)-dependent manner, from endothelial cells and activates vascular K+ channel(s) with the predominant evidence suggesting K(Ca) (iberiotoxin and/or apamin sensitive) though this remains to be absolutely confirmed. A number of studies also indicate that a cytochrome P-450 metabolite of arachidonic acid, namely an epoxyeicosatrienoic acid, may serve as the chemical messenger between endothelial and vascular smooth muscle cells. Evidence confirming that there is chemical transmission between endothelial and vascular smooth muscle cells is, however, minimal. Although significant progress has been recently made, much needs to be discovered concerning the nature, synthesis, release, vascular effects as well as the role of EDHF in normal and diseased vascular tissue.