It has recently been appreciated that NO, a molecule previously known to play a physiologic role in blood pressure regulation, is a major effector molecule of macrophage cytotoxicity against a variety of microbial targets, including protozoan and helminth parasites. NO production by macrophages is arginine dependent and catalyzed by a cytokine-inducible form of the NO synthase. This activity is positively controlled by several up-regulatory stimuli (including IFN-gamma, TNF-alpha, IL-2) and negatively controlled by others (principally IL-10, IL-4, TGF-beta). Other cell types, such as endothelial cells and hepatocytes, display a similar capacity for NO production in response to cytokine stimulation. In murine models of leishmaniasis and schistosomiasis, in vivo NO synthesis correlates with protective immunity against infection. The effector molecule that plays a similar role in cell-mediated immunity in man has not yet been identified.