After achievement of adequate anticoagulation, the natural history of acute pulmonary emboli ranges from near total resolution of vascular perfusion to long-term persistence of hemodynamically consequential residual perfusion defects. The persistence of perfusion defects is necessary, but not sufficient, for the development of chronic thromboembolic pulmonary hypertension (CTEPH). Approximately 30% of patients have persistent defects after 6 months of anticoagulation, but only 10% of those with persistent defects subsequently develop CTEPH. A number of clinical risk factors including increasing age, delay in anticoagulation from symptom onset, and the size of the initial thrombus have been associated with the persistence of perfusion defects. Likewise, a number of cellular and molecular pathways have been implicated in the failure of thrombus resolution, including impaired fibrinolysis, altered fibrinogen structure and function, increased local or systemic inflammation, and remodeling of the embolic material by neovascularization. Treatment with fibrinolytic agents at the time of initial presentation has not clearly improved the frequency or degree of recovery of pulmonary vascular perfusion. A better understanding of the interplay between clinical risk factors and pathogenic mechanisms may enhance the ability to prevent and treat CTEPH in the future.