The presence of gastric acid plays a critical role in the mechanisms of NSAIDs/aspirin-associated gastric and duodenal mucosal injury and ulceration. The role of gastric acid and its relationship to NSAIDs/aspirin in mucosal damage, ulcer and ulcer complications continues to be an important concern because of the increasing worldwide use of NSAIDs and aspirin. Acid suppression continues to be an important prevention strategy for NSAID-associated gastric and duodenal ulcer and ulcer complications. While a coxib or an NSAID and PPI in combination are considered to have comparable safety profiles, the evidence from direct comparisons in high-risk patients is limited, and the cardiovascular safety of coxibs and NSAIDs remains a concern especially in patients with a high risk of cardiovascular disease. An evaluation of individual gastrointestinal and cardiovascular risks and benefits, selection of the most appropriate NSAID and dose for each particular patient should always be emphasized. Twice daily PPI is more appropriate to protect a patient who is taking NSAIDs twice daily. PPI co-therapy is still recommended in patients receiving dual antiplatelet treatment, although conflicting results have been reported about adverse drug interactions between PPIs and clopidogrel.