Clopidogrel owes its antiplatelet effect to irreversible inhibition of the purinergic platelet receptor, P2Y12. It is estimated that approximately 4%-30% of patients treated with conventional doses of clopidogrel do not display adequate platelet response. Moreover, patients with low response to clopidogrel may be at higher risk for atherothrombotic events. Clopidogrel, being a prodrug, requires oxidation by the hepatic cytochrome P450 (CYP450)3A to generate an active metabolite.The level of CYP3A4 activity has been shown to correlate with the inhibitory effect of clopidogrel on platelet aggregation in healthy volunteers. However, CYP3As expression and activity vary among individuals. It is estimated that most of this variability is caused by individual genetic makeup.Polymorphisms of the P2Y12 receptor may also play a role in the variability in clopidogrel response. The P2Y12-H2 haplotype was associated with higher maximal platelet aggregation in response to adenosine diphosphate (ADP) as compared to the P2Y12-H1 haplotype probably due to an increase in the number of receptors on the platelet surface. It has also been suggested that carriers of the H2 haplotype might be at higher risk of developing peripheral artery disease.