Acute pulmonary embolism (PE) presents as a constellation of clinical syndromes with a variety of prognostic implications. Patients with acute PE who have normal systemic arterial blood pressure and no evidence of right ventricular (RV) dysfunction have an excellent prognosis with therapeutic anticoagulation alone. Normotensive acute PE patients with evidence of RV dysfunction are categorized as having submassive PE and comprise a population at intermediate risk for adverse events and early mortality. Patients with massive PE present with syncope, systemic arterial hypotension, cardiogenic shock, or cardiac arrest and have the highest risk for short-term mortality and adverse events. The majority of deaths from acute PE are due to RV pressure overload and subsequent RV failure. The goal of fibrinolysis in acute PE is to rapidly reduce RV afterload and avert impending hemodynamic collapse and death. Although generally considered to be a life-saving intervention in massive PE, fibrinolysis remains controversial for submassive PE. Successful administration of fibrinolytic therapy requires weighing benefit versus risk. Major bleeding, in particular intracranial hemorrhage, is the most feared complication of fibrinolysis. Alternatives to fibrinolysis for acute PE, including surgical embolectomy, catheter-assisted embolectomy, and inferior vena cava (IVC) filter insertion, should be considered when contraindications exist or when patients have failed to respond to an initial trial of fibrinolytic therapy. Patients with massive and submassive PE may be best served by rapid triage to specialized centers with experience in the administration of fibrinolytic therapy and the capacity to offer alternative advanced therapies such as surgical and catheter-assisted embolectomy.