Endothelium-derived hyperpolarizing factor (EDHF), which induces membrane hyperpolarization of vascular smooth muscle, is a vasorelaxant factor, which, like nitric oxide (NO), is synthesized and released by the endothelium. First reported in 1988, it remains unidentified. Candidates include endothelial K+ and hydrogen peroxide, and involve electrical communication through myoendothelial gap junctions. EDHF is released in response to neurohumoral factors and physiologic stimuli, including shear stress and pulsatile stretch. In peripheral resistance arterioles, its relative contribution to endothelium-dependent relaxation exceeds that of NO. EDHF-mediated relaxation is a major player in the physiologic regulation of peripheral vascular resistance and tissue perfusion. Its identification is critical to the full elucidation of the role of endothelial factors in maintaining vascular homeostasis...