Because of the widespread use of nonsteroidal anti-inflammatory drugs (NSAIDs), NSAID-related gastrointestinal (GI) complications are recognized as the most prevalent drug toxicity in the United States. The withdrawal of 2 selective cyclooxygenase-2 (COX-2) inhibitors (agents specifically developed to reduce ulcer complications) from the US market owing to adverse cardiovascular events has made reducing ulcer risk more important than ever for patients receiving NSAID treatment. In addition, the impact of aspirin, implicated by itself as a cause of serious adverse GI events and in combination with NSAIDs as a source of incremental risk, remains under-appreciated. Balancing the cardiovascular risks of selective COX-2 inhibitors with the higher GI risks associated with conventional NSAIDs remains a major clinical challenge. Gastro-protective therapy, such as with a proton pump inhibitor, is beneficial in patients receiving NSAIDs, but despite current treatment recommendations, this "ounce of prevention" remains substantially underused for patients at risk.