Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most widely used classes of medications worldwide, available both through prescription and over the counter (OTC). Although these drugs are highly effective for pain, gastrointestinal (GI) complications may occur. Risk factors for GI complications from NSAIDs have been well studied, and the highest risk exists among the elderly and patients with a history of GI bleeding or complications. The increasingly widespread use of aspirin for both primary and secondary cardiovascular prophylaxis has also drawn attention to the potential increase in GI complications. Several strategies may minimize NSAID-mediated GI complications, including the use of drugs that do not injure the gut, such as acetaminophen or a low-dose opiate. The cyclooxygenase-2 (COX-2) inhibitors, which cause approximately 50% fewer GI complications than traditional NSAIDs, may also be used, although their cardiovascular safety has recently come into question. Antacid therapy with proton pump inhibitors (PPIs) may also be used to reduce NSAID-related dyspepsia and upper GI complications. Misoprostol is also effective in preventing NSAID-related complications, but is not as well tolerated. In any patient, the risk-benefit ratio must be assessed to determine the appropriate therapies to minimize GI complications resulting from daily aspirin therapy.