NSAIDs, including both aspirin and nonaspirin NSAIDs, are among the most frequently used drugs, and their use may result in serious adverse gastrointestinal outcomes and significant medical costs. The increased risks for adverse upper GI hemorrhage and peptic ulcer disease associated with NSAID use have been demonstrated in observational studies and clinical trials; an overview of these results is presented in this article. The magnitude of these risks should play an important role in clinical decision making and should influence decisions regarding the use of this class of drugs.