Optimal thrombolytic therapy in acute myocardial infarction must aim to achieve early and complete reperfusion of the infarct related coronary artery. Establishment of normal coronary flow (Thrombolysis in Myocardial Infarction [TIMI] grade 3) is the key correlate of improved survival. Three large-scale clinical trials, the Reteplase Angiographic Phase II International Dose-finding Study (RAPID 1), the Reteplase vs Alteplase Patency Investigation During Acute Myocardial Infarction Study (RAPID 2), and the International Joint Comparison of Thrombolytics Study (INJECT), have evaluated the comparative efficacy and safety of reteplase, a new, rapid-acting thrombolytic agent that offers the practical clinical convenience of bolus dosing. RAPID 1 and 2 demonstrated that reteplase was associated with superior early coronary artery patency rates compared with alteplase, whether alteplase was infused over 3 h or over 90 min. Further, the TIMI 3 flow rates achieved in reteplase-treated patients at 60 min were comparable to those achieved at 90 min with the accelerated alteplase dosing regimen. The INJECT trial showed that reteplase resulted in comparable mortality and clinical benefits to those achieved with streptokinase. All three studies demonstrated that reteplase therapy was not associated with an increase in bleeding complications or other adverse clinical events. The simple double-bolus regimen of reteplase administration may permit earlier initiation of thrombolysis with fewer dosing errors than with continuous infusion regimens and thus afford a reduction in the morbidity and mortality risks in patients with acute myocardial infarction.