Arterial tone is dependent upon the net contribution between vasoconstricting and vasodilating influences. One of these vasodilators, nitric oxide (NO), plays a major role in blood pressure regulation. NO is produced by a family of NO synthase that use L-arginine as the substrate. Therapy with organic nitrates, such as nitroglycerin and isosorbide dinitrate, and sodium nitroprusside generates NO directly. NO, produced endogenously or derived from exogenous agents, achieves vasorelaxation through activation of soluble guanylate cyclase, which initiates a cascade of events that relaxes the smooth muscle cell. Not surprisingly, derangement of the endogenous nitrovasodilator pathways can produce both hypertension and hypotension. Diminished NO production may participate integrally in the pathogenesis of hereditary salt-sensitive hypertension in the Dahl/Rapp rat, hypertension in patients with renal failure on dialysis, and hypertension from cyclosporin therapy. Overstimulation of the inducible L-arginine: NO pathway by bacterial endotoxin and cytokines may account for hypotension in septic shock and cytokine therapy. As understanding of the L-arginine: NO pathways improves, new therapeutic modalities that alter these pathways in humans may be developed.