Background and Purpose: Pulmonary hypertension (PH) is a disease of hyperplasia of pulmonary vascular cells. The pentose phosphate pathway (PPP) – a fundamental glucose metabolism pathway – is vital for cell growth. Because treatment for PH is inadequate, our goal was to determine whether inhibition of glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme of the PPP, prevents maladaptive gene expression that promotes smooth muscle cell (SMC) growth, reduces pulmonary artery remodeling, and normalizes hemodynamics in experimental models of PH. Experimental Approach: PH was induced in mice by exposure to 10% oxygen (Hx) or weekly injection of vascular endothelial growth factor receptor blocker (Sugen5416 (SU); 20 mg.kg-1) during exposure to hypoxia (Hx+SU), and in rats by injecting SU, exposure to 3 weeks Hx, and then 5 weeks normoxia. G6PD inhibitor (PDD4091;1.5 mg kg-1) was injected daily during exposure to Hx. We measured right ventricular (RV) pressure and left ventricular (LV) pressure-volume relationships, and gene expression in lungs of normoxic, Hx, and Hx+SU, and G6PD inhibitor-treated, mice and rats. Key Results: RV systolic and end-diastolic pressures were higher in Hx and Hx+SU than normoxic-control mice. Hx and Hx+SU decreased expression of epigenetic modifiers, increased hypomethylation of the DNA, and induced aberrant gene expression in lungs. G6PD inhibition decreased maladaptive expression of genes and SMC growth, reduced pulmonary vascular remodeling, and decreased RV pressures, compared to untreated PH groups. Conclusions and Implications: Inhibition of G6PD efficaciously reduces RV pressure overload in Hx and Hx+SU mice and rats and appears to be a safe pharmacotherapeutic strategy.