BACKGROUND Percutaneous coronary intervention (PCI) is a proven treatment option for patients with acute coronary syndrome (ACS). Treatment of this patient population with antiplatelet therapy before and after percutaneous coronary intervention (PCI) is ever-changing. Combining clopidogrel, a thienopyridine, with aspirin has become the gold standard dual antiplatelet therapy. However, new research reveals several limitations with clopidogrel, including potential drug-drug interactions, slow onset of action, irreversibility of platelet inhibition, and a wide array of patient responses. A new thienopyridine, prasugrel, has been approved and supported by the current guidelines for its faster onset of action, lack of significant drug-drug interaction, and consistent patient response. OBJECTIVE This article will present a background of ACS and the 2 thienopyridines (prasugrel and clopidogrel), provide a comprehensive analysis of 4 recent trials comparing the 2 drugs in patients with ACS undergoing PCI, and pose 2 further research questions involving the genetic variability and the optimum duration of antiplatelet therapy after PCI. CONCLUSIONS The American College of Cardiology/American Heart Association guidelines support prasugrel in patients specifically with ST-segment elevation myocardial infarction, non-ST-segment elevation myocardial infarction, previous or current stent restenosis or occlusion, and diabetes. Relative contraindications in patients using prasugrel include bleeding tendencies, age greater than 75 years, and body weight less than 60 kg. Absolute contraindications of prasugrel use include history or current stroke and active bleeding. With further research looking at duration of treatment and cardiovascular events with prasugrel and clopidogrel, clinicians will be able to make more evidence-based decisions. CONCLUSIONS Prasugrel has been shown to be an effective alternative to clopidogrel in treating patients with dual antiplatelet therapy for ACS requiring PCI. Awareness of the risks and benefits when deciding to prescribe clopidogrel or prasugrel for patients with ACS during and after PCI will promote patient safety, improve patient outcomes, and support evidence-based practice.