A hundred years after the introduction of aspirin as the first effective anti-inflammatory drug, problems of tolerability still beset this class of drugs, in particular, gastrointestinal toxicity. Despite this, NSAIDs are among the most widely used and prescribed drugs world-wide. Many agents have been used to counteract these side-effects with varying degrees of success and acceptance. Although the central mechanism of NSAID action, reduced prostaglandin production by cyclooxygenase (COX) inhibition, was first described 25 years ago, the recent discovery of a second, inducible form of cyclooxygenase, COX-2, has stimulated research and interest in producing NSAIDs that are inherently safer whilst maintaining efficacy. Specific COX-2 inhibitors, the first of which has recently been marketed in the UK, offer real hope as safer NSAIDs and this may be realised when drugs with even greater specificity become available. However, long-term safety and efficacy need to be demonstrated in clinical practice, and questions remain unanswered about possible physiological roles for COX-2. Other approaches to improving the safety of NSAIDs, including profound acid suppression and nitric oxide donation, may prove to be as successful in this rapidly changing field.