The US Surgeon General estimates that 100,000 to 180,000 deaths occur annually from acute pulmonary embolism (PE) in the United States. The case of Ms A, a 60-year-old woman with acute PE and right ventricular dysfunction (submassive PE), illustrates the clinical challenge of identifying this high-risk patient population and determining when more aggressive immediate therapy should be pursued in addition to standard anticoagulation. The clinical examination, electrocardiogram, cardiac biomarkers, chest computed tomography, and echocardiography can be used to risk stratify patients with acute PE. Current options for more aggressive intervention in the treatment of patients with acute PE who are at increased risk of an adverse clinical course include systemic fibrinolysis, pharmacomechanical catheter-directed therapy, surgical pulmonary embolectomy, and inferior vena cava filter insertion. Determination of the optimal duration of anticoagulation and lifestyle modification to reduce overall cardiovascular risk are critical components of the long-term therapy of patients with acute PE.