Anticoagulation has been shown to improve mortality in acute pulmonary embolism (PE). Initiation of anticoagulation should be considered when PE is strongly suspected and the bleeding risk is perceived to be low, even if acute PE has not yet been proven. Low-risk patients with acute PE are simply continued on anticoagulation. Severely ill patients with high-risk (massive) PE require aggressive therapy, and if the bleeding risk is acceptable, systemic thrombolysis should be considered. However, despite clear evidence that parenteral thrombolytic therapy leads to more rapid clot resolution than anticoagulation alone, the risk of major bleeding including intracranial bleeding is significantly higher when systemic thrombolytic therapy is administered. It has been demonstrated that right ventricular dysfunction, as well as abnormal biomarkers (troponin and brain natriuretic peptide) are associated with increased mortality in acute PE. In spite of this, intermediate-risk (submassive) PE comprises a fairly broad clinical spectrum. For several decades, clinicians and clinical trialists have worked toward a more aggressive, yet safe solution for patients with intermediate-risk PE. Standard-dose thrombolysis, low-dose systemic thrombolysis, and catheter-based therapy which includes a number of devices and techniques, with or without low-dose thrombolytic therapy, have offered potential solutions and this area has continued to evolve. On the basis of heterogeneity within the category of intermediate-risk as well as within the high-risk group of patients, we will focus on the use of systemic thrombolysis in carefully selected high- and intermediate-risk patients. In certain circumstances when the need for aggressive therapy is urgent and the bleeding risk is acceptable, this is an appropriate approach, and often the best one.