The ability of NO to control microcirculatory blood flow, maintain vascular integrity, and act as an antiinflammatory mediator appears to be dependent on endothelial-derived NO. The function of excess NO production by iNOS in sepsis and septic shock is unclear but iNOS-derived NO may contribute to systemic hypotension. The use of more specific inhibitors for iNOS will help to define the role of iNOS in sepsis. Modulation of the pulmonary NO-cGMP signal transduction system following LPS treatment results in hyporesponsiveness to inhaled NO and impaired pulmonary vascular response to vasodilators, suggesting potential mechanisms of the pulmonary dysregulation observed in sepsis.