OBJECTIVE To critically evaluate the published literature assessing the safety and efficacy of thrombolytic therapy for massive and submassive pulmonary embolism (PE). METHODS A search of human trials in the English-language (September 2017) was conducted through the MEDLINE database using the following terms: PE, tissue plasminogen activator, tenecteplase, and alteplase. 67 unique articles were identified, of which 24 clinical trials discussing clinical outcomes related to administration of either intravenous tenecteplase or alteplase were included. RESULTS Thrombolytic therapy with anticoagulation significantly reduced mortality compared to anticoagulation alone in massive PE. In submassive PE, thrombolytics reduced the rate of right ventricular dysfunction and hemodynamic collapse; however, there is an increased risk of major and minor bleeding with no benefit on long-term functional outcomes. CONCLUSIONS Patients with massive PE should receive thrombolytics when no major contraindications to therapy exist. Patients with submassive PE at highest risk for progression to hemodynamic instability should receive anticoagulation and be monitored for clinical deterioration. If an imminent risk of hemodynamic instability or cardiac arrest occurs, thrombolytics should be administered if no contraindications exist. Net mortality benefit and risk of bleeding must be considered when deciding to administer thrombolytic therapy in massive or submassive PE.