The endothelium-derived relaxing factor that mediates the endothelium-dependent vasodilatation first observed in 1980 has been identified as nitric oxide (NO). In addition to the endothelium, NO is formed in other cells such as neuronal cells of the brain (where it mediates synoptic plasticity), peripheral nonadrenergic noncholinergic (NANC) nerves (where it acts as an atypical neurotransmitter relaxing vascular and nonvascular smooth muscle), and various specialized epithelial cells. Other cell types such as macrophages and smooth muscle cells can be induced with bacterial endotoxin and/or cytokines to synthesize large amounts of the radical. At low concentrations, NO is an inter- and intracellular messenger molecule whose target enzyme is the soluble isoform of guanylyl cyclase. At high concentrations, the NO radical has cytostatic effects on parasitic microorganisms and tumor cells. In the vascular system, endothelium-derived NO is a physiologically significant vasodilator and inhibitor of platelet aggregation and adhesion. NANC nerve-derived NO may also contribute to vasodilatation. In addition, NO can prevent leukocyte adhesion to the endothelium by interfering with the adhesion molecule CD11/CD18, and NO has been shown to inhibit the proliferation of vascular smooth muscle cells. In sepsis and during cytokine therapy, a different NOS is induced in the vascular wall (presumably in smooth muscle cells) where it synthesizes large amounts of NO that contribute to the massive vasodilatation and shock. © 1993.