Successfully utilized contemporary pulmonary embolism thrombolysis reverses right heart failure rapidly and safely. This therapeutic approach may lower mortality from pulmonary embolism and reduce morbidity from chronic pulmonary hypertension. Pulmonary embolism thrombolysis remains a debatable indication because large clinical trials using survival as an endpoint have not been carried out. Instead, thrombolysis trials have been undertaken with surrogate endpoints such as reduction in clot burden, reduction in pulmonary arterial pressure, and improvement in right ventricular function. In an era where hundreds of thousands of myocardial infarction patients have participated in thrombolysis trials that focus on survival as the principal endpoint, the much smaller trials of PE thrombolysis have not been sufficiently definitive to achieve a consensus. Pharmaceutical companies have not considered this area of investigation to be a good return on investment, because PE is a much less common problem than acute coronary syndromes. No government funding agency has targeted PE thrombolysis as a priority for clinical research. Currently, the only contemporary thrombolytic regimen for pulmonary embolism that is approved by the Food and Drug Administration is tissue plasminogen activator, in a dose of 100 mg/2 h. New thrombolytic agents under development for pulmonary embolism include reteplase, saruplase, and recombinant staphylokinase. Future clinical trials will require multicenter collaboration and focus on clinically relevant endpoints such as reduction of mortality and recurrent venous thromboembolism.