Antiplatelet therapy with aspirin and clopidogrel, aimed to inhibit platelet function and reactivity, is the recommended standard of care for reducing the occurrence of cardiovascular events in patients with acute coronary syndromes undergoing percutaneous coronary intervention with stent implantation. However, major adverse cardiovascular events including the severe complication of stent thrombosis occur in patients taking dual antiplatelet therapy. Clopidogrel requires intestinal absorption and hepatic conversion to active metabolite by several cytochrome P450 isoenzymes, among which the CYP2C19 plays a pivotal role; then, the active metabolite inhibits ADP-stimulated platelet activation by irreversibly binding to the P2Y12 receptor. Several factors interacting with each other are involved in determining the variability of individual response to clopidogrel. Nongenetic factors include chronic persistent factors (e.g., age, diabetes) and acute phase transient factors (e.g., inflammation). Among the numerous genetic variants investigated, recently, the loss-of-function CYP2C19*2 polymorphism has been associated with a decreased metabolization of clopidogrel, poor antiaggregant effect, and increased cardiovascular events. In high risk vascular patients, who experience percutaneous coronary intervention with stent implantation, the CYP2C19*2 polymorphism is a strong predictor of the adverse cardiovascular events and particularly stent thrombosis. Ongoing and future prospective studies evaluating if an antiplatelet treatment tailored on individual characteristics of patients — genetic variants, platelet phenotype, drug-drug interactions, as well as traditional and procedural risk factors - are now urgently awaited in order to define the optimal therapeutic strategies and management providing the best benefit for a given individual patient.