The endothelium functions as a semipermeable membrane separating the blood from the body and allowing the transport of macromolecules from the blood to the interstitial space. The endothelium secretes a number of diffusible substances. These include endothelium-derived relaxing factor (EDRF), endothelium-derived hyperpolarizing factor (EDHF), and prostacyclin, in addition to vasoconstrictors including endothelin, angiotensin, and endothelium-derived contracting factor. EDRF is now known to be nitric oxide, or a closely related molecule, which affects signaling by stimulation of soluble guanylate cyclase, causing increased intracellular levels of cyclic guanosine monophosphate (cGMP), in turn leading to relaxation of vascular smooth muscle as well as a variety of additional effects that include altered function of platelets and cardiac myocytes. Nitric oxide can be made available to cellular elements in two ways: by endogenous synthesis via one or more of the three nitric oxide synthases now known to exist in mammalian species; or by exogenous administration of pharmacologic sources of nitric oxide, usually as organic nitrate vasodilators that can be metabolically converted to biologically activated nitric oxide. This process appears to require free sulfydryl groups. The metabolic machinery necessary to convert organic nitrates to a biologically active form exists mainly in the vasculature and not in the myocardium. Numerous studies have demonstrated that the presence of coronary artery disease is associated with interruption of the endogenous production of nitric oxide. Under these circumstances, exogenous nitrates still produce coronary vasodilation as well as relaxation of vascular smooth muscle in the periphery. Other articles in this supplement will focus on the vascular effects of nitric oxide and nitrovasodilators; this article will conclude with a brief discussion of the role of the nitric oxide pathway in the control of cardiac autonomic responsiveness and the potential role of cytokines and the nitric oxide pathway to impair the ability of the myocardium to respond to catecholamines or other stimuli with a normal increase in contractile function.