The importance of the dissolution and prevention of thrombosis in treating patients with ST-segment elevation myocardial infarction (STEMI) has motivated the development of novel therapies targeting platelet aggregation and thrombus formation. In contemporary practice, the current challenge is the integration of these therapies into reperfusion strategies that may include fibrinolytic therapy or percutaneous coronary revascularization (PCI). Evidence from clinical trials shows that addition of glycoprotein IIb/IIIa inhibition to PCI for treatment of STEMI has substantially lowered the incidence of recurrent ischemic events and improved early survival. In contrast, current trials evaluating a strategy termed facilitated PCI, or planned early PCI after pharmacologic reperfusion therapy, have presently demonstrated an increased risk of bleeding events and mortality. Additional trials have extended the role of antithrombotic agents to STEMI that previously were reserved for patients undergoing elective revascularization or among those treated with non-ST-segment elevation acute coronary syndromes. For example, the recent studies have demonstrated the benefit of clopidogrel treatment among STEMI patients treated with fibrinolysis in reducing the incidence of infarct artery reocclusion and improving early survival. Other anticoagulants under investigation in the management of STEMI include enoxaparin, bivalirudin, and fondaparinux. This review summarizes the current status of pharmacologic and invasive strategies for the treatment of STEMI and describes recent and ongoing directions for clinical investigation.