Nonsteroidal anti-inflammatory drugs (NSAIDs) are effective in treating inflammation, pain and fever, but their cardiovascular, renal and gastrointestinal toxicity can result in significant morbidity and mortality to patients. Techniques for minimizing the adverse risks of NSAIDs include avoiding use of NSAIDs where possible, particularly in high-risk patients; keeping NSAID dosages low; prescribing modified-release and enteric-coated NSAIDs; prescribing cyclooxygenase-2-selective inhibitors where appropriate; monitoring for early signs of side effects; prescribing treatments designed to minimize NSAID side effects; and developing new therapeutic strategies beyond the inhibition of cyclooxygenase. All of the above strategies can be useful in reducing the risk of NSAID complications. The optimal use and management of NSAIDs involves an individualized paradigm approach to establish efficacy with optimal tolerability given the patient risk factors for adverse events.