Rationale: Pulmonary arterial hypertension (PAH) is a progressive disease characterized by an elevation in the mean pulmonary artery pressure leading to right heart failure and a significant risk of death. Alterations in two TGF signaling pathways, bone morphogenetic protein receptor II (BMPR II) and the TGF-receptor I, ALK1, have been implicated in the pathogenesis of PH. However, the role of TGF-family signaling in pulmonary hypertension and pulmonary vascular remodeling remains unclear. Objectives: To determine whether inhibition of TGF signaling will attenuate and reverse monocrotaline induced pulmonary hypertension. Methods: We have used an orally active small molecule TGF inhibitor, SD-208, to determine the functional role of this pathway in monocrotaline-induced pulmonary hypertension (MCT-PH). Measurements and main results: The development of MCT-PH was associated with increased vascular cell apoptosis, which paralleled TGF signaling as documented by pSMAD2 expression. Inhibition of TGF signaling with SD208 significantly attenuated the development of the pulmonary hypertension and reduced pulmonary vascular remodeling. These effects were associated with decreased early vascular cell apoptosis, adventitial cell proliferation, and matrix metalloproteinase expression. Inhibition of TGF signaling with SD-208 in established MCT-PH resulted in a small but significant improvement in hemodynamic parameters and medial remodeling. Conclusions: These findings provide evidence that increased TGF-signaling participates in the pathogenesis of experimental severe pulmonary hypertension.