Thrombolysis is an effective causal therapy for patients suffering from massive pulmonary embolism or acute myocardial infarction. In more than 70% of patients with cardiac arrest, one of these two diseases is the underlying cause of deterioration. Nevertheless, because of the fear of severe bleeding complications, thrombolytic therapy during cardiopulmonary resuscitation (CPR) has been contraindicated. Increasing clinical experience and data from open studies now suggest that thrombolysis during CPR can contribute to hemodynamic stabilization and survival in patients with massive pulmonary embolism and acute myocardial infarction, after conventional CPR procedures have been performed unsuccessfully. After administration of thrombolytic agents, some patients have been stabilized even after more than 90 minutes of CPR. Besides the specific causal action of thrombolytic agents at the site of pulmonary emboli and coronary thrombosis, experimental data indicate that thrombolysis during CPR can improve microcirculatory reperfusion, which may be most important in the brain. In accordance with these data, marked activation of blood coagulation without adequate activation of endogenous fibrinolysis has been demonstrated during reperfusion after cardiac arrest. Massive coagulation activation with subsequent fibrin formation is responsible for microcirculatory reperfusion disorders, and thrombolytic therapy may be indicated. However, no controlled studies are available on this therapeutic concept. Because the risk of bleeding complications is potentially associated with the administration of thrombolytic agents, although this occurs far less than anticipated, thrombolysis during CPR is presently a treatment strategy that can be performed on an individual basis. Whether thrombolysis during CPR can improve survival rates and neurologic outcomes should be addressed in randomized, controlled trials.