With the establishment of thrombosis as the cause of myocardial infarction, the pivotal role of thrombolytics and primary angioplasty has evolved. Large randomized trials with innovative methodologies have examined the role of these reperfusion therapies in the management of acute coronary syndromes. Intravenous thrombolytic therapy decreases mortality in a broad group of patients with acute myocardial infarction. The GUSTO trial established intravenous tissue plasminogen activator (tPA) used in combination with intravenous heparin as the most effective thrombolytic therapy. Importantly, the time to achieve reperfusion is crucial to the mortality benefit observed, and rapid attainment of Thrombolysis in Myocardial Infarction (TIMI) trial grade 3 flow is achieved in only approximately 55% of patients who receive thrombolytics. Reocclusion, cellular damage, and microvascular dysfunction may contribute to less than optimal results. Percutaneous transluminal coronary angioplasty (PTCA) may be the preferred method of acute reperfusion therapy based on higher rates of TIMI grade 3 flow and lower rates of reocclusion and recurrent myocardial infarction. However, marked variation exists in outcomes and utilization rates among individual institutions, and the benefits of PTCA have not been consistently maintained at 6 months. The use of stents and anticoagulants may improve results, and pre-PTCA strategies also are under investigation. Limitations remain in the efficacy of current reperfusion therapies, supporting the search for improved thrombolytic agents, primary angioplasty, stents, and antithrombotics with the goal of improving TIMI 3 flow rates and achieving reperfusion more rapidly.