NSAIDs are among the most frequently prescribed medications worldwide and are used in many medical conditions to alleviate pain and inflammation. Their use has continued despite long-known gastrointestinal adverse events and mucosal damage throughout the gastrointestinal tract. The damage is not limited to the upper gastrointestinal tract, and lower gastrointestinal adverse events are as common as those in the upper gastrointestinal tract. COX-2 inhibitors carry less gastrointestinal side effects than nonselective NSAIDs, but the cardiovascular profile is comparable to that of nonselective NSAIDs and may limit the use of both classes of drugs. Clinicians should be aware of potential adverse events and approaches to improve the safety profile including eradication of Helicobacter pylori (H. pylori) infection, coadministration of proton pump inhibitors (PPIs), using the lowest required dose and frequency of dosing, choosing an NSAID with a better safety profile, considering both gastrointestinal and cardiovascular risks, and individualizing the care of the patient. Education of the patient and ensuring adherence to prescribed medication are also key to optimizing the risk/benefit associated with the use of NSAIDs.