The endothelium possesses the ability to modulate vascular tone by the release of vasodilator and vasoconstrictor substances, among them endothelium-derived relaxing factor (EDRF) and endothelin. Abnormalities in EDRF generation were demonstrated in various cardiovascular pathophysiological states, specifically atherosclerotic vascular disease, congestive heart failure, and essential and pulmonary hypertension. Moreover, increases in plasma endothelin concentration have been reported as well in these disease states. When these observations are taken together, these states may be characterized by an attenuated release of EDRF, whereas the release of endothelin is augmented. An imbalance between EDRF and endothelin may contribute to the alteration in vascular tone characteristic of cardiovascular disease. The following review summarizes the present knowledge of the role of EDRF and endothelin in such disease processes.