When a previously healthy adult experiences atraumatic cardiac arrest, providers must quickly identify the etiology and implement potentially lifesaving interventions such as advanced cardiac life support. A subset of these patients develop cardiac arrest or periarrest due to pulmonary embolism (PE). For these patients, an early, presumptive diagnosis of PE is critical in this patient population because administration of thrombolytic therapy may significantly improve outcomes. This article reviews thrombolysis as a potential treatment option for patients in cardiac arrest or periarrest due to presumed PE, identifies features associated with a high incidence of PE, evaluates thrombolytic agents, and systemically reviews trials evaluating thrombolytics in cardiac arrest or periarrest. Despite potentially improved outcomes with thrombolytic therapy, this intervention is not without risks. Patients exposed to thrombolytics may experience major bleeding events, with the most devastating complication usually being intracranial hemorrhage. To optimize the risk-benefit ratio of thrombolytics for treatment of cardiac arrest due to PE, the clinician must correctly identify patients with a high likelihood of PE and must also select an appropriate thrombolytic agent and dosing protocol.