This review summarizes the principal therapeutic responses to the preferential COX-2 NSAID, nimesulide, in treating musculo-skeletal joint symptoms and various acute and chronic pain conditions and the mode of action in relation to therapy in these states. In extensive studies in laboratory animal models and clinical trails in patients nimesulide has been found to have potent analgesic, anti-inflammatory and anti-pyretic activities. It is approved for use in over 50 countries worldwide (including those in the EU, South and Central America, China, India and some other South-East Asia) for the treatment of acute pain, the symptomatic treatment of painful osteoarthritis and primary dysmenorrhoea. Its mode of action in these states is related to the preferential inhibition of the production of cyclo-oxygenase-2 (COX-2) and other inflammatory mediators whose production is controlled by stimulation of cyclic-3 ,5'-adenosine monophosphate (cAMP); this means that nimesulide is a multi-factorial drug in controlling inflammation and pain. The adverse reaction profile of nimesulide is, in general, like that of other NSAIDs. It does, however, have relatively low occurrence of gastro-intestinal (GI) side effects which is related to its low propensity to inhibit the physiologically important COX-1 in the GI mucosa and important physicochemical properties (high pKa of 6.5 and lipophilicity) as well as inhibiting of mast cell derived histamine and acid secretion in the stomach. In contrast with the coxibs, nimesulide has not been found to have appreciable cardiovascular toxicity.