Clopidogrel combined with aspirin is the mainstay of antiplatelet therapy for patients who present with acute coronary syndromes as well as following either bare metal or drug-eluting stent placement. Limitations of clopidogrel therapy include the relatively long time course required to achieve maximal inhibition of platelet aggregation, individual variability in response to its effect, the risk of bleeding during its administration, and the irreversible nature of P2Y12 receptor binding, which leads to a prolonged time course for recovery of platelet function following discontinuation of clopidogrel. Several investigational P2Y12 receptor antagonists have pharmacological properties that may overcome some or all of these limitations. These novel agents such as prasugrel, AZD6140, and cangrelor are in advanced stages of clinical development for potential use in patients with coronary artery disease.