The use of thrombolytic therapy to treat AMI has reawakened interest in thrombolysis for acute pulmonary embolism (PE). We have investigated the use of recombinant human tissue-type plasminogen activator (rtPA) in patients with acute PE. In an open label study, rtPA achieved more than 90% efficacy and safety. In a trial comparing rtPA with an FDA-approved dose of urokinase (UK), rtPA appeared more rapid and safer. We are now conducting a comparative trial of rtPA with a novel dosing regimen of UK. In addition, a concurrent trial is comparing rtPA vs heparin for improvement in right ventricular function, assessed by echocardiography, among PE patients. However, the greatest challenge in PE research is to undertake a large-scale trial that compares thrombolysis and heparin for reduction of clinically relevant end points such as mortality and recurrent PE.