Platelet activation is a pivotal event in the pathophysiology of acute coronary syndromes (ACS) and percutaneous coronary intervention (PCI) and has a substantial impact on the outcomes in these settings. Aggressive implementation of antiplatelet therapy has significantly decreased adverse cardiovascular events, such as death, myocardial infarction (MI), stroke, and repeat revascularization. Although the widespread use of aspirin has contributed to this improvement, many patients continue to have a significant risk of recurrent events during the ensuing months to years. The advent of other antiplatelet agents, notably the thienopyridine clopidogrel bisulfate has heralded a new era of combined antiplatelet blockade, offering the hope of better outcomes. Recently, clinical trials have tested the use of dual oral antiplatelet blockade and have shown impressive results. Notably, the Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial found that dual therapy with clopidogrel and aspirin in ACS reduced adverse cardiovascular events by 20% at 1 year (p < 0.001). The PCI-CURE substudy of CURE and the Clopidogrel for the Reduction of Events During Observation (CREDO) trial demonstrated that these benefits extend to patients undergoing both urgent and elective PCI. This article will explore the current role of and controversies in oral antiplatelet therapy after ACS and PCI.