At present, high-risk pulmonary embolism represents a cardiovascular emergency burdened with high in-hospital mortality and characterized by acute right ventricular dysfunction and hemodynamic impairment. In addition to circulatory support and anticoagulation, thrombolytic therapy has become the cornerstone of the treatment in patients presenting with this condition. Despite the recommendations, a consistent proportion of patients does not currently receive thrombolytic therapy. Although performed in a limited number of patients, transcatheter and surgical embolectomy procedures are an alternative or synergistic therapeutic strategy to thrombolysis, enabling a prompt resolution of right ventricular volume overload. In this review, data from the literature are discussed with the aim of defining an algorithm for the treatment of high-risk patients.