The debilitating disease pulmonary arterial hypertension (PAH) is characterized by an elevation in blood pressure in the lung arteries caused by vessel-blocking vascular-cell proliferation. This vascular remodeling is thought to result in part from defects in the endoplasmic reticulum stress response and mitochondrial dysfunction in pulmonary artery smooth muscle cells. In this issue of Science Translational Medicine, Sutendra et al. show that the vascular remodeling protein Nogo-B plays a role in the development of PAH in response to hypoxia-induced stress. The new findings finger Nogo-B as a possible therapeutic target for PAH.