Non-steroidal anti-inflammatory drugs (NSAIDs) causes extensive damage to the gastrointestinal (GI) tract. The underlying mechanisms of gastric injury include topical irritant actions that disrupt the epithelial barrier, as well as the inhibition of cyclo-oxygenase (COX), which is predominantly the COX-1 isoform in the mucosa. This damage can be attenuated by antisecretory agents or by mucosal protective agents such as the synthetic prostanoids or nitric oxide (NO) donors. Compounds designed to attenuate topical irritancy, or have protective agents incorporated, such as NO-containing NSAIDs, the CINODs (cyclo-oxygenase-inhibiting NO-donating drugs) show reduced mucosal injury. NSAIDs also cause injury in the small intestine, which appears to result from initial COX inhibition, with subsequent translocation of indigenous bacteria, induction of NO synthase and production of the cytotoxic moiety, peroxynitrite. The COX-2 selective agents, the coxibs, which inhibit prostanoid biosynthesis at inflammatory sites, but not the endogenous protective prostanoids in the gut formed by COX-1, have proved so far to be a successful therapeutic approach to reducing NSAIDs GI damage. The clinical outcome of the use of the second generation of coxibs, and the newer NO NSAIDs is now awaited.