The free radical nitric oxide (NO) is synthesized from the guanidino group of L-arginine by a family of enzymes termed NO synthase (NOS). Hemorrhagic shock leads to an inhibition of NO production by the calcium-dependent, endothelial NOS (ecNOS), which may lead to maldistribution of blood flow leading to, eg, coronary, renal, and cerebral ischemia and may enhance the adhesion of neutrophil granulocytes and platelets to the endothelial surface. Prolonged periods of hemorrhagic shock are associated with the induction of a calcium-independent isoform of NOS in a variety of organs and in the vascular smooth muscle. The formation of large quantities of NO by inducible isoform of NOS (iNOS) contributes to the delayed vascular decompensation and to the hyporeactivity of the vasculature to vasoconstrictor agents. An impairment of NO formation by the ecNOS has been demonstrated in various models of traumatic shock, whereas there is good experimental evidence supporting the hypothesis that an enhanced formation of NO contributes to the pathophysiology of experimental thermal injury and anaphylactic shock. We speculate that a pharmacological modulation of NO biosynthesis which either enhances NO concentration in the vicinity of endothelium (ie, NO donors) or inhibits NO overproduction following iNOS expression (ie, iNOS-selective NOS inhibitors) may become novel therapies to improve the outcome of patients with circulatory shock of various etiologies.