Gastroduodenal mucosa possesses an array of defensive mechanisms and nonsteroidal anti-inflammatory drugs (NSAIDs) have a deleterious effect on most of them. This results in a mucosa less able to cope with even a reduced acid load. The presence of acid appears to be a conditio sine qua non for NSAIDs injury. Acid not only injures the mucosa by back-diffusing from the lumen to cause tissue acidosis but also serves to increase drug absorption. Although much of the experimental work has been done using salicylates, it is now well accepted that almost all the NSAIDs are capable of causing mucosal damage. These compounds appear to cause gastro-duodenal damage, by two main mechanisms: a physiochemical disruption of the gastric mucosal barrier and a systemic inhibition of gastric mucosal protection, through inhibition of cyclo-oxygenase activity of gastro-intestinal (GI) mucosa. A reduced synthesis and secretion of mucus and bicarbonate, an impairment of mucosal blood flow and an increase of acid secretion represent the main consequences of NSAID-induced prostaglandin (PG) deficiency. Additional mechanisms which may add to the damage have been demonstrated. These include uncoupling of oxidative phosphorylation, reduced mucosal cell proliferation and DNA synthesis as well as neutrophil activation. Recent work has demonstrated that, after administration of NSAIDs, neutrophil adherence to the vascular endothelium occurs, with consequent reduced mucosal perfusion and release of tissue-damaging mediators. Since PGs are well-established modulators of inflammatory response, it is evident that NSAIDs induce damage to GI tract via a mechanism identical to that by which they exert their anti-inflammatory action. In this context, it is very difficult to imagine an effective NSAID completely devoid of gastrointestinal side effects. Although NSAIDs with tissue-selective effects on cyclo-oxygenase are available and compounds with reduced topical irritancy have been developed, gastroduodenal damage still represents an important effect of this class of drugs, because no NSAID is completely devoid of GI side effects.