Although there is increasing awareness of the important disease burden associated with chronic thromboembolic pulmonary hypertension (CTEPH), the pathogenesis of the disease has not been fully elucidated, and factors contributing to its development remain poorly defined. Although current data suggest that CTEPH does not result from traditional, known thrombophilia or defective plasma fibrinolysis, it has been suggested that levels of Factor VIII and antiphospholipid antibodies (alongside increased lupus anticoagulant), two thrombophilic factors associated with recurrent thrombosis, are elevated in association with CTEPH. Differences in the expression of type-1 plasminogen activator-inhibitor in CTEPH thrombi (compared with thrombi seen in acute pulmonary embolism) suggest that in situ thrombosis within vascularized fibromuscular obstructions may favor the persistence of thrombi, contributing to disease progression. Additional risk factors have been evaluated in patients with CTEPH, including blood groups (which reflect genetically determined erythrocyte-bound oligosaccharide structures) and lipoprotein (a). Certain medical conditions (splenectomy, ventriculo-atrial shunt/(infected) intravenous lines, acute pulmonary embolism, and chronic inflammatory states) have been established as independent risk factors for CTEPH. In particular, the link between splenectomy and CTEPH has gained considerable attention, with speculation that abnormal post-splenectomy erythrocyte activities or abnormal platelet activation may be involved. Although some patients may be genetically susceptible to pulmonary arterial hypertension, genetic variants linked with CTEPH have yet to be determined. Improved understanding of risk factors for CTEPH is an important goal, allowing better targeting of at-risk groups, facilitation of appropriate intervention, and potential limitation of disease progression.