Clopidogrel plus aspirin is considered the antiplatelet treatment of choice in patients with acute coronary syndrome, whether or not they are undergoing a percutaneous coronary intervention (PCI). The same treatment is mandatory in all patients undergoing a PCI with stent implantation. Clopidogrel is a pro-drug that needs metabolic activation through a cytochrome P450-dependent pathway, with an extensive involvement of the CYP 2C19 isoenzyme. Proton pump inhibitors (PPIs) reduce the risk of gastrointestinal bleeding in patients receiving dual antiplatelet therapy. In the past two years some scientific evidences have suggested a possible negative interference of PPIs on antiplatelet effect of clopidogrel because of the competitive inhibition of the CYP 2C19 isoenzyme. Few studies testing platelet reactivity in patients receiving both clopidogrel and a PPI have demonstrated a reduced inhibitory effect of the association on platelet aggregation. Moreover, results from retrospective observational studies have shown a higher incidence of major cardiovascular events in patients receiving both clopidogrel and PPIs. These data have not been confirmed neither by the only prospective randomized study comparing clopidogrel plus omeprazole with clopidogrel alone, nor by the retrospective analysis of the TRITON TIMI 38 trial, where PPIs did not affect the clinical outcome of patients given clopidogrel or prasugrel. Nevertheless both the US Food and Drug Administration (FDA) and the European Medicines Agency (EMEA) have discouraged the concomitant use of clopidogrel and PPIs. Important questions concerning a true interference between the two classes of drugs still remain unanswered and need to be addressed by adequately powered studies.