Patients with cardiac arrest after fulminant pulmonary embolism (PE) have a very poor prognosis. Conventional cardiopulmonary resuscitation (CPR) is frequently unsuccessful because it does not treat the underlying condition. Although thrombolysis is an effective therapeutic option for patients with acute PE, this treatment has traditionally been withheld during CPR because of the anticipated risk of severe hemorrhagic complications associated with chest compressions. This chapter focuses on the mechanisms of action of thrombolytic therapy during CPR after acute PE on the basis of experimental and clinical data. In fact, most data suggest a significant improvement of overall and neurological outcome in patients receiving thrombolysis during CPR after massive PE. Although the use of thrombolytics is indeed associated with an increased incidence of hemorrhagic complications in this setting, critical bleeding complications are rare and do not seem to outweigh the potential benefits of this therapeutic option. Therefore, thrombolytic therapy should not be withheld in patients suffering cardiac arrest after massive PE, particularly if conventional CPR has failed to show immediate success and other treatment options (e.g., surgical embolectomy) are not available.