Dual antiplatelet therapy (DAPT) with aspirin and a P2Y₁₂ receptor blocker is the standard of care to prevent recurrent ischemic event occurrence in patients undergoing percutaneous intervention. Glycoprotein IIb/IIIa receptor inhibitors are used in addition to DAPT in the highest-risk clinical settings. The persistent occurrence of ischemic events in the presence of DAPT and the irrefutable demonstration of clopidogrel response variability are two potent arguments against the widely practiced nonselective or “one-size-fits-all” strategy of administering clopidogrel therapy and provides a strong rationale for monitoring clopidogrel therapy. New, potent P2Y₁₂ inhibitors such as prasugrel and ticagrelor are associated with greater platelet inhibition, faster onset of action, and better overall clinical outcomes compared with clopidogrel, but are associated with more non–surgery-related bleeding than clopidogrel. The inhibition of the platelet thrombin receptor may provide additional benefits in attenuating ischemic event occurrence in selected high-risk patients treated with DAPT.