Inhibition of the platelet P2Y12 receptor plays an important role in the prevention of thrombotic complications of acute coronary syndrome and percutaneous coronary interventions. Despite clinical benefits with clopidogrel therapy in these high risk patients, efficacy of clopidogrel is limited by slow onset of action, variability in platelet inhibitory response and potential drug–drug interactions. Importantly, suboptimal platelet inhibition by clopidogrel is associated with worse prognosis. This underscores the need for alternate antiplatelet treatment strategies. A number of novel P2Y12 antagonists are approved or in advanced development and some have demonstrated superior platelet inhibition effect, clinical outcomes, and safety profile than clopidogrel in patients with acute coronary syndrome. The aim of this manuscript is to provide an overview on the current status in P2Y12 receptor inhibition and to review the pharmacology and clinical development of four of these agents: prasugrel, cangrelor, ticagrelor, and elinogrel.