The platelet P2Y12 receptor plays a critical role in sustaining ADP-mediated platelet aggregation. Drawbacks of the thienopyridine clopidogrel, a prodrug of an irreversible P2Y12 antagonist, include the need for two-step metabolism to its active form and partial hydrolysis to its inactive metabolite. Both contribute to high variability in the degree of platelet inhibition and the irreversibility of binding complicates both acute and planned invasive treatments when rapid offset of antiplatelet activity is desired. Novel P2Y12 antagonists include the thienopyridine prasugrel and the selective, direct, reversible antagonists cangrelor (iv) and AZD6140 (oral). Prasugrel, also an irreversible antagonist, requires only one-step metabolism to active form and achieves greater inhibition of platelet aggregation (IPA) than clopidogrel. Recently published data indicate that this translates into improved efficacy. Like clopidogrel, prasugrel relies on new platelet generation for offset of effect. The direct reversible antagonists bind directly to the receptor, and the degree of IPA closely follows plasma drug concentrations. In addition to permitting more rapid offset of effect and greater and more consistent IPA than clopidogrel, direct reversible antagonists may exert additional beneficial effects via blockade of P2Y12 in vascular smooth muscle cells. Reversible antagonists also appear to exhibit a wider therapeutic window, showing reduced bleeding time prolongation per given degree of antithrombotic effect in experimental models. Ongoing large-scale Phase 3 clinical trials are examining cangrelor in patients with acute coronary syndromes (ACS) also undergoing percutaneous coronary intervention (PCI) and AZD6140 in ACS patients being treated with medical therapy, PCI, or coronary artery bypass grafting.