Nonsteroidal anti-inflammatory drugs (NSAIDs) belong to the most frequently used drugs. The discovery of an inducible isoform of cyclo-oxygenase (COX-2) has led to an intensive worldwide search and the introduction of selective COX-2 inhibitors. In this review, recent advances in understanding the mechanism of action of NSAIDs and, in this context, clinical findings on NSAID-induced gastrointestinal side effects are summarized. This knowledge is important for the effective treatment of pain and inflammation, as well as for preventing serious and sometimes lethal gastrointestinal side effects.