Fibrinolysis has used tissue plasminogen activator (tPA) alone ever since it replaced Streptokinase (SK) in therapeutic fibrinolysis. This was based on the belief that tPA was responsible for natural fibrinolysis. When prourokinase plasminogen activator was discovered (prouPA) in 1980, it was believed to be an extravascular plasminogen activator. This has turned out to be a mistaken concept. Out of the three fibrin-bound plasminogens responsible for fibrinolysis, only the first one, the one which initiates fibrinolysis, is activated by tPA. The other two are activated by prouPA and two chain uPA (urokinase) respectively. Therefore, the functions of tPA and prouPA are analogous to those of the starter and the fuel in a car. By mimicking this natural model for therapy, fibrinolysis can be made much safer because high dose infusions of tPA, that can cause bleeding at vascular repair sites, are eliminated.