Dual antiplatelet therapy with aspirin and clopidogrel is among the most efficacious treatment for patients after acute coronary syndromes and for those who have had a percutaneous coronary intervention and coronary stent implantation. Patients who are treated with dual antiplatelet therapy are usually also ordered medications that reduce the secretion of gastric acid (such as H2 receptor blockers or proton pump inhibitors [PPIs]) in order to decrease the risk of gastrointestinal bleeding and dyspepsia. Numerous observational studies reported that omeprazole (a PPI) attenuates the antiplatelet activity and clinical effectiveness of clopidogrel and causes adverse cardiovascular events. Based on these findings, several medical agencies in the world have issued communications regarding the negative interaction between clopidogrel and PPIs, urging clinicians to evaluate the need for starting treatment with a PPI in patients taking clopidogrel. There are studies that reported contradicting findings, suggesting that there is no significant interaction between clopidogrel and PPIs. Only one prospective, randomized, double-blind, placebo-controlled clinical trial examined the interaction between clopidogrel and omeprazole and did not demonstrate cardiovascular harm among the patients who were treated with clopidogrel and omeprazole, as compared to those who were treated with clopidogrel and placebo. In this article, the authors review the current studies that reported a possible drug-drug interaction between clopidogrel and PPIs, particularly omeprazole.