Approximately 10% of all patients with acute pulmonary embolism (PE) die within the first three months after diagnosis. However, PE is not universally life-threatening, but covers a wide spectrum of clinical severity and death risk. Thrombolytic treatment is indicated patients with acute massive PE who are at high risk for early death, i.e. those patients who present with arterial hypotension and shock. On the other hand, low molecular-weight heparin or fondaparinux is adequate treatment for most normotensive patients with PE. Recombinant tissue plasminogen activator, given as 100 mg infusion over 2 h, is the treatment of choice for patients with PE, although older regimens using urokinase or streptokinase are also efficacious. Beyond the relatively small numbers of patients with massive, high-risk PE as a target population for thrombolysis, there is increasing awareness of the need for risk stratification of normotensive patients and the search for an intermediate-risk group (also called submassive PE). Recent meta-analyses of cohort studies suggest that imaging of the right ventricle or biomarkers of myocardial injury alone may be insufficient for guiding therapeutic decisions. Instead, accumulating evidence appears to support strategies which combine the information provided by an imaging procedure with a biomarker test. These data provide the rationale for a large multinational randomized trial which has set out to determine whether normotensive patients with right ventricular dysfunction, detected by echocardiography or computed tomography, plus evidence of myocardial injury as indicated by a positive troponin test, may benefit from early thrombolytic treatment. This study, which is underway in 13 European countries, will enroll a total of 1000 patients and will be completed in 2012. Together with a parallel trial currently being conducted in the United States, it will hopefully answer the question whether thrombolysis is indicated in submassive PE, thus terminating a 40-year-old debate and filling an important gap in our management concept for acute pulmonary embolism.