Since its identification as the active metabolite of nitroglycerin identical to endothelium derived relaxing factor, in mid-eighties, nitric oxide has been found over-all distributed in all body tissues implicated in many normal functions as well as pathophysiologic states, so that it has been aptly called biological jack-ofall- trades. Initial clues indicating a role of nitric oxide in the physiopathology of pain concerned inflammatory pain. So far in this reference, a large amount of data has arisen supporting arguably that nitric oxide is involved in peripheral nociceptor sensitization as well as in plastic changes at spinal and supraspinal levels, during inflammatory painful disorders. Nitric oxide involvement in neuropathic pain has been also recognized, although relevant research is less extended compared to that concerning inflammatory pain. In addition nitric oxide has been considered to play a major role in the headache phase of migraine with aura through vascular and neurogenic mechanisms. Data about nitric oxide involvement in pain pathophysiology have set a trend for testing the L-argininenitric oxide pathway products as predictors in monitoring the course of certain painful pathologic conditions and their response to treatment, in recent clinical studies.