P2Y₁₂ antagonists, in combination with aspirin, significantly reduce thrombotic and ischemic events in patients presenting with an acute coronary syndrome and in patients undergoing percutaneous coronary intervention. The thienopyridine clopidogrel is a prodrug that requires bioactivation by the cytochrome P450 (CYP) system in order to exert its antiplatelet effect. Common genetic polymorphisms that reduce the catalytic activity of the CYP2C19 isoenzyme decrease circulating levels of active metabolite, reduce levels of platelet inhibition, and increase the risk of ischemic events in clopidogrel-treated patients. Herein, we review the impact of the CYP2C19 genotype on the pharmacokinetics and pharmacodynamics of clopidogrel, the association between CYP2C19 genotype and clinical outcome, and present the rationale for the implementation of CYP2C19 genotyping to individualize antiplatelet therapy in clinical practice.