Dual antiplatelet therapy with aspirin and clopidogrel is the standard of care for patients with acute coronary syndrome (ACS) and those undergoing percutaneous coronary intervention (PCI). It is well established that inhibition of platelet aggregation reduces the risk of recurrent thrombotic events and stent thrombosis. However, some patients show a reduced antiplatelet response to standard clopidogrel loading (300 mg) and maintenance (75 mg day−1) doses, which has been associated with poorer patient outcomes. Pharmacodynamic and pharmacokinetic studies show that higher-than-standard clopidogrel dosing strategies facilitate more rapid platelet inhibition of a greater intensity as a result of greater plasma concentrations of the clopidogrel active metabolite. Recently completed studies suggest that in patients with ACS undergoing PCI, higher-than-standard clopidogrel dosing regimens provide greater inhibition of platelet function and improved clinical outcomes with a small but significant increase in major bleeding. Newer, more potent antiplatelet agents such as prasugrel and ticagrelor are other alternative strategies that result in more rapid, greater inhibition of platelet function and better outcomes than standard-dose clopidogrel. Whether platelet reactivity-guided therapy or genotyping for cytochrome P450 polymorphisms is useful in managing patients needs to be further defined. Most importantly, early and effective antiplatelet therapy results in the best short- and long-term outcomes for patients with ACS or those undergoing PCI. © 2011 Wiley-Liss, Inc.