Abstract Tissue plasminogen activator (tPA) was approved for therapeutic fibrinolysis in 1987, when it replaced streptokinase (SK) for the treatment of acute myocardial infarction (AMI). It remains the fibrinolytic of choice today although over the last decade fibrinolysis has been replaced by percutaneous coronary intervention (PCI) whenever possible. However, PCI is a technically demanding procedure that is time-consuming whereas for AMI “time is myocardium” and only rapid reperfusion will salvage function of ischemic myocardium. Fibrinolysis is the simplest fastest method, but it requires both plasminogen activators, the second one being urokinase plasminogen activator (uPA), the native form of which is a proenzyme, prouPA. A combination of a 5 mg bolus of tPA followed by a prouPA matches the natural paradigm and was shown to be more effective safer than tPA monotherapy. Activator gene knockout studies also showed that both activators are required, but that uPA rather than tPA was the dominant one, as well as the one neglected for the past 33 years.