Nonsteroidal anti-inflammatory drugs (NSAIDs) have huge prescription volumes, for two main reasons: the aging of the population is increasing the prevalence of diseases that respond to NSAIDs, such as osteoarthritis; and NSAIDs are highly effective drugs that contribute crucially to the management of many diseases. In France, the number of physician orders that include an NSAID is estimated at 25 to 30 million per year. Nevertheless, the use of NSAIDs is limited by adverse effects. The gastrointestinal tract is the main target of NSAID toxicity, and NSAID therapy is among the leading causes of bleeding from upper gastrointestinal ulcers. Adverse events targeting the lower gastrointestinal tract are also of concern, although they receive less attention. To effectively prevent NSAID toxicity, it must be recognized that the risk of adverse events can be diminished but not eliminated. Therefore, the risk/benefit ratio must be carefully evaluated at each prescription. A number of risk factors should be emphasized. Thus, the risk increases with age, and there is a sharp risk increase at 60 years of age. Other risk factors include a history of ulcers (most notably with bleeding), the use of high NSAID dosages, Helicobacter pylori infection, and the concomitant use of antiplatelet agents. Minimizing NSAID-related gastrointestinal toxicity requires a careful risk factor evaluation; selection of the most appropriate NSAID and NSAID dosage; and, in some patients, prophylactic gastroprotective therapy, for instance with a proton pump inhibitor. Gastrointestinal symptoms either have no value for predicting gastrointestinal events or occur too late to serve as alarm signals. The toxicity advantages of cyclooxygenase-2 inhibitors seem modest and do not eliminate the need for this rational prescription strategy.