NSAIDs are widely prescribed for the treatment of musculoskeletal disorders. The gastrointestinal tract, predominantly the stomach, bears the brunt of their side-effects. The basis of this toxicity is certainly multifactorial, with a wide range of local effects and mucosal defences being implicated. This review will highlight: (1) the epidemiology of NSAID-induced gastrointestinal toxicity; (2) their effects on prostaglandins, and the phenomenon of cytoprotection; (3) effects on neutrophil function; (4) effects on mucosal blood flow; (5) responses of the mucosa to damage (restitution, adaptation, and regenerative repair); (6) the relevance of growth factors; (7) interactions with Helicobacter pylori in ulcerogenesis, and finally (8) the effects of NSAIDs on the small intestine and colon.