Antiplatelet agents remain the cornerstone in the primary and secondary therapeutic intervention for cardiovascular disease. Some patients may be subjected to a year or more of dual antiplatelet therapy to reduce the risk of subsequent cardiovascular events. Patients on antiplatelet therapy have an increased risk of gastrointestinal bleeding; however, not all patients benefit from concomitant acid suppressive therapy. This review will provide an overview of the pharmacology of antiplatelet agents and outline patient risk profiles that ought to be considered when considering prophylactic therapy to reduce gastrointestinal toxicity. In addition, we discuss the current risk-reduction strategies intended to mitigate against the potential for related gastroduodenal injury.