A variety of conditions can lead to the development of pulmonary arterial hypertension (PAH). Current treatments can improve symptoms and reduce the severity of the hemodynamic abnormality, but most patients remain quite limited, and deterioration in their condition necessitates a lung transplant. This review discusses current experimental and clinical studies that investigate the pathobiology of PAH. An emerging theme is the consideration of ways in which one might reverse the advanced occlusive structural changes in the pulmonary circulation causing PAH. The current debate concerning the role of regeneration through stem cells is presented. This review also highlights investigations in a number of laboratories relating the pathobiology of PAH to mutations causing loss of function of bone morphogenetic protein receptor II in patients with familial PAH, as well as sporadic cases.