Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most common self-administered and prescribed drugs taken in the United States. From 30% to 50% of those using these medications experience some degree of gastrointestinal (GI) side effect. Independent of NSAID use, a majority of athletes suffer GI symptoms, most of which has been documented in endurance athletes. Studies of NSAID use in patients with chronic osteo- and rheumatoid arthritis have defined a set of factors that can identify those who are at higher risk of serious GI events. Using such a model, clinicians can choose either to discontinue NSAID use, or prescribe a lower-risk NSAID or coxib (rofecoxib, celecoxib), prophylaxis with misoprostol, or proton pump inhibitor. Coxibs have been designed to decrease GI ulceration and bleeding by selective inhibition of cyclooxygenase-2, and offer an option for patients at high risk of GI hemorrhage. There are data suggesting that rofecoxib may be associated with an increased risk of myocardial infarction, and until further data are available, caution should be used when considering its prescription to patients at high risk of cardiovascular events.