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Clopidogrel remains the most widely used P2Y₁₂ receptor inhibitor worldwide and is often used in combination with aspirin for secondary prevention in patients with arterial disease. The drug is associated with a wide response variability with one on three patients exhibiting little or no inhibition of adenosine diphosphate-induced platelet aggregation. It is a prodrug that is mainly metabolized by hepatic cytochrome P450 (CYP) 2C19. Patients who carry a CYP2C19 loss-of-function (LoF) allele have reduced metabolism of clopidogrel that is associated with reduced platelet inhibition compared to non-carriers that is associated with increased risk for thrombotic event occurrences, particularly, stent thrombosis. The United States Food and Drug Administration (US FDA) issued a black box warning in the clopidogrel label highlighting the importance of presence of CYP2C19 LOF allele during the insufficient metabolism of clopidogrel and availability of other potent P2Y₁₂ inhibitor for the treatment in CYP2C19 poor metabolizers. Clinical trials have conclusively demonstrated greater anti-ischemic benefits of prasugrel/ticagrelor in the treatment of patients carrying the CYP2C19 LoF allele. However, uniform use of these more potent P2Y₁₂ inhibitors has been associated with greater bleeding and cost, and lower adherence. The latter information provides a strong rationale for personalizing P2Y₁₂ inhibitor therapy based on the laboratory determination of CYP2C19 genotype. However, cardiologists have been slow to take up pharmacogenetic testing possibly due to lack of provider and patient education, clear cardiology guidelines and, and lack of positive results from adequately sized randomized clinical trials. However, current evidence strongly supports genotyping of patients who are candidates for clopidogrel. Physicians should strongly consider performing genetic tests to identify LoF carriers and treat these patients with more pharmacodynamically predictable P2Y₁₂ inhibitors than clopidogrel.