Upper gastrointestinal disease induced by use of nonsteroidal anti-inflammatory drugs (NSAIDs) remains a major problem that affects a broad segment of the population, given the frequent use of these drugs by prescription and over the counter. The emergence of the cyclooxygenase (COX)-2 selective inhibitors (coxibs) has introduced a new option that may result in less upper gastrointestinal disease. Recent large studies have demonstrated this advantage, with the caveat that concurrent use of low-dose aspirin may mitigate this benefit. Unfortunately, the relatively high cost of the coxibs makes them not cost-effective unless confined to certain higher-risk populations. Finally, even newer versions of NSAIDs, such as nitric oxide (NO)-releasing aspirin and the COX-inhibiting NO donors, are potential alternatives to traditional NSAIDs with less upper gastrointestinal toxicity.