Pulmonary embolism (PE) is a prevalent condition that may account for > 300,000 deaths annually in the United States alone. Although thrombolytics have been studied as a treatment for acute PE since the 1960s, to date there have been only 11 randomized controlled trials comparing thrombolytic therapy to conventional anticoagulation, and the numbers of patients included in these trials has been small. Many studies confirm that thrombolytic therapy leads to rapid improvement in hemodynamic aberrations associated with PE, and this approach to massive PE with cardiogenic shock is a guideline-based practice. It is widely accepted that acute PE without associated right ventricular (RV) dysfunction or hemodynamic instability can be readily managed with standard anticoagulation. The appropriate therapy for submassive PE (PE associated with RV dysfunction but preserved systemic arterial BP) remains an area of contention, and definitive data proving mortality benefit in this setting are lacking. Further efforts at risk stratification may better determine who is in need of aggressive therapy. This article reviews historical aspects of and current evidence for thrombolytic therapy in acute PE with specific attention to bleeding risk, and data regarding hemodynamic parameters and mortality. We also discuss risk stratification techniques and propose a clinical algorithm for the incorporation of thrombolytic therapy.