Clopidogrel is an antiplatelet drug that is used in patients who have had previous cerebrovascular events, acute coronary syndromes, or percutaneous coronary interventions (PCI). Clopidogrel therapy is associated with bleeding complications, and gastrointestinal bleeding has been reported as one of the most common life-threatening complications. This review focuses on the possible interaction between clopidogrel and CYP2C19, a known site of PPI metabolism. This interaction attenuates the antiplatelet effect of clopidogrel and seems to worsen cardiovascular outcome. Alternative concomitant therapy is also discussed.