Antiplatelet therapy to reduce the risks of recurrent myocardial infarction and restenosis after primary percutaneous coronary intervention is critically important to optimize the early treatment of ST-segment elevation myocardial infarction (STEMI). Traditionally, acetylsalicylic acid (ASA; aspirin) has been recommended for patients with suspected STEMI, but this agent targets only one of several pathways of platelet aggregation. Antiplatelet agents with different inhibitory mechanisms may act synergistically with ASA. Glycoprotein IIb/IIIa inhibitors are generally not used with fibrinolytic agents in acute STEMI management; indeed, glycoprotein IIb/IIIa inhibitors plus bolus fibrinolytics increase the risk of intracranial hemorrhage. Aggressive antiplatelet therapy with clopidogrel reduces mortality in STEMI patients and offers significant clinical benefits, without an associated increase in major bleeding events. Recent trials support the development of an early and aggressive approach to more complete platelet inhibition using clopidogrel, in combination with ASA, for patients with STEMI.