Nitric oxide (NO), a free radical molecule, produced by NO synthase (NOS) in the body exerts a number of pathophysiological actions due to its chemical reactivity. Low amounts of NO (nM) normally produced by constitutive NOS play a critical role in different physiological events such as vasodilation and neurotransmission. Higher amounts of NO ( micro M) locally and spatially produced by inducible NOS during inflammation act as double-edged sword exerting either beneficial or detrimental effects. Recently, new vision on the biological role of NO has been proposed based on the possible cross-talk between constitutive and inducible NOS. Accordingly, normally produced low amounts of NO may be involved in the regulation of NF-kappaB activation and successively the expression of inducible NOS. Under normal conditions NF-kappaB activation is suppressed by low amounts of NO. Under conditions in which massive amounts of NO produced by inducible NOS act detrimentally, NO-elicited down-regulation of NF-kappaB activation is compromised due to the drop in NO at the early phase of inflammation caused by inactivation of constitutive NOS. Any treatment which counterparts the drop in NO, therefore, may present a new approach either in preventing or in treating inflammatory diseases.