Prostaglandins have numerous mucosal protective properties, impairment of which contribute to NSAID injury. It is not clear which is the most important injurious factor affecting patients taking NSAIDs. Is it the NSAID itself, either by topical toxicity and/or production of toxic mediators or does the patient become more sensitive to NSAIDs as a result of some other luminal component, such as acid or bile acids, food (by physical or chemical mechanisms) or accompanying alcohol? Intrinsic irritancy/toxicity probably accounts for the greater mucosal toxicity of aspirin, although it is not clear whether this is due to a direct (non-prostaglandin-dependent) effect on mucus or bicarbonate secretion, membrane integrity, interference with intermediary metabolism or the production of toxic products. Similarly, the relationship of irritancy to the symptom of dyspepsia, to which patients on aspirin are prone, is as yet not well understood. While strategies for short-term protection of experimental animals and humans are well established, protection against important, but relatively rare clinical events, is more difficult to study and much less well understood. In particular, the importance of the ability of NSAIDs to exacerbate bleeding, independent of injury, has been largely neglected in the context of presentation with haematemesis and melaena.