Sepsis is a heterogeneous class of syndromes caused by a systemic inflammatory response to infection. Septic shock, a severe form of sepsis, is associated with the development of progressive damage in multiple organs, and is a leading cause of patient mortality in intensive care units. Despite important advances in understanding its pathophysiology, therapy remains largely symptomatic and supportive. A decade ago, the overproduction of nitric oxide (NO) had been discovered as a potentially important event in this condition. As a result, great hopes arose that the pharmacological inhibition of NO synthesis could be developed into an efficient, mechanism-based therapeutic approach. Since then, an extraordinary effort by the scientific community has brought a deeper insight regarding the feasibility of this goal. Here we present in summary form the present state of knowledge of the biological chemistry and physiology of NO. We then proceed to a systematic review of experimental and clinical data, indicating an up-regulation of NO production in septic shock; information on the role of NO in septic shock, as provided by experiments in transgenic mice that lack the ability to up-regulate NO production; effects of pharmacological inhibitors of NO production in various experimental models of septic shock; and relevant clinical experience. The accrued evidence suggests that the contribution of NO to the pathophysiology of septic shock is highly heterogeneous and, therefore, difficult to target therapeutically without appropriate monitoring tools, which do not exist at present.