Endothelial-dependent relaxation of vascular smooth muscle cells evoked by a number of agonists, including cholinomimetics and substance P, is often accompanied by an increase (repolarization and/or hyperpolarization) in the membrane potential. This change in membrane potential appears predominantly to reflect the action of an endothelial-derived hyperpolarizing factor (EDHF), which is distinct from NO (or endothelial-derived relaxing factor), and is discussed in this article by Chris Garland and colleagues. In large conducting arteries, EDHF may provide a secondary system to NO, which assumes primary importance in some disease states such as pulmonary hypertension and atherosclerosis. However, in small resistance arteries (100-300 microns), EDHF appears to be a major determinant of vascular calibre under normal conditions, and may therefore be of primary importance in the regulation of vascular resistance.