Cardiovascular diseases are the most common cause of mortality and morbidity accounting for more than 40% of total mortality in Western countries, most of which is due to acute coronary syndromes (ACS), including ST and non- ST elevation myocardial infarction. An optimal pharmacological approach in these patients is of major importance with a particular emphasis on the antiplatelet regimen, which remains the cornerstone of the initial ACS treatment at hospital admission and during percutaneous coronary interventions (PCI). This review briefly discusses the pathogenesis of ACS, and updates the available pharmacological antithrombotic strategies with a particular focus on aspirin and clopidogrel resistance, which has caused major concern, especially in the modern era of interventional cardiology. Persistent platelet reactivity despite aspirin or clopidogrel intake is probably a risk factor for the recurrence of ischemic events. Despite a lack of uniformly accepted definitions of aspirin and clopidogrel resistance, we provide an objective description of what is already proved and what remains to be established. In clopidogrel poor-responders, preliminary data suggest that increasing the loading dose might be beneficial prior to PCI, while trials on the potential benefit of an increased maintenance dose after PCI are ongoing. Overall, data on the mechanisms and the management of platelet hyperactivity or antiplatelet drug biological resistance are still scarce and further studies are needed.