Nonsteroidal anti-inflammatory drugs (NSAIDs) are a heterogeneous class including acetylsalicylic acid (ASA) and various other nonselective and selective inhibitors of cyclooxygenase. These drugs are most commonly used as analgesics, anti-inflammatory agents and antipyretics, and low-dose ASA because of its effect on platelet aggregability is widely used for the secondary prevention of thromboembolic events. The most common undesirable effects of NSAID are toxic effects in the upper gastrointestinal (GI) tract, primarily gastric erosions and ulcers. Approximately half of the patients who regularly take NSAIDs have gastric erosions, and 15-30% have ulcers when they are examined endoscopically. The risk of GI injury varies widely in relationship to some clinical features, e.g. history of GI events, age, concomitant anticoagulant (e.g. warfarin), steroid or antiplatelet use (e.g. tienopiridins), and NSAIDs dose. This review discusses mechanisms of NSAIDs toxicity, identification of patients at highest risk for development of NSAID-induced GI complications, use of co-therapies in prevention or therapy ofNSAIDs toxicity, and finally classes of NSAIDs with improved GI safety profiles.