In the past 100 years aspirin has demonstrated its value as an analgesic, anti-inflammatory, and antithrombotic agent. However, by 1938, it was clear that aspirin was gastrotoxic. Non-steroidal anti-inflammatory drugs (NSAIDs), developed since the 1960s, failed to achieve the goal of "a safer aspirin". The demonstration that inhibition of prostaglandin synthesis via a cyclo-oxygenase (COX) enzyme was central to both the therapeutic and toxic effects of aspirin and non-aspirin NSAIDs appeared to establish the principle of no gain without pain. This link may have been broken by drugs that selectively inhibit the inducible COX-2 enzyme. The COX enzyme is now a target of drug interventions against the inflammatory process. Might the "safe aspirin" be here at last?