By inhibiting prostaglandin synthesis, nonsteroidal anti-inflammatory drugs (NSAIDs) compromise gastroduodenal defense mechanism including blood flow and mucus/bicarbonate secretion. This has led to NSAIDs being the most widely reported drug cause of adverse events. While NSAIDs also cause dyspepsia, inhibition of prostaglandin synthesis may reduce this from even higher levels that would otherwise prevail and mask ulcer-related dyspepsia, making anticipatory management difficult. On average, the risk of ulcer complications increases 4-fold, resulting in 1.25 additional hospitalizations per 100 patient-years according to one estimate. Older patients, those with a past history, and those taking anticoagulants or corticosteroids are at higher risk. Risk is dose dependent and is lower with ibuprofen at low doses than with other NSAIDs. It is unlikely that Helicobacter pylori increases the risk, and under some circumstances it may be protective. Selective inhibitors of the inducible cyclooxygenase 2 spare gastric mucosal prostaglandin synthesis and do not damage the gastric mucosa. Their place in therapy, compared with use of misoprostol or proton pump inhibitors, is currently emerging. Future competitors may include nitric oxide-donating, zwitterionic, or R-enantiomer NSAIDs.