Pulmonary hypertension (PH) and cancer pathology share growth factor- and MAPK stress-mediated signaling pathways resulting in endothelial and smooth muscle cell dysfunction and angioproliferative vasculopathy. In this study, we assessed sorafenib, an antineoplastic agent and inhibitor of multiple kinases important in angiogenesis (VEGFR1-3, PDGFR-, Raf-1 kinase) as a potential PH therapy. Two PH rat models were used: a conventional hypoxia-induced PH model and an augmented PH model combining dual VEGFR1, 2 inhibition (SU5416, single 20 mg/kg injection) with hypoxia. In addition to normoxia-exposed controls, four groups were maintained in 10% FiO₂ for 3.5 weeks (hypoxia/vehicle, hypoxia/SU5416, hypoxia/sorafenib and hypoxia/SU5416/ sorafenib). Compared to normoxic controls, rats exposed to hypoxia/SU5416 developed hemodynamic and histologic evidence of severe PH while rats exposed to hypoxia alone displayed only mild elevations in hemodynamic values (pulmonary vascular and right ventricular pressures). Sorafenib treatment (daily gavage, 2.5 mg/kg) prevented hemodynamic changes and demonstrated dramatic attenuation of PH-associated vascular remodeling. Compared to normoxic controls, expression profiling (Affymetrix platform) of lung RNA obtained from hypoxia (FDR of 6.5%)- and hypoxia/SU5416 (FDR, 1.6%)- challenged rats yielded 1019 and 465 differentially-regulated genes (fold change >1.4), respectively. A novel molecular signature consisting of 38 differentially-expressed genes between hypoxia/SU5416 and hypoxia/SU5416/sorafenib (FDR 6.7%), was validated by either real-time RT-PCR or immunoblotting. Finally, immunoblotting studies confirmed the up-regulation of the MAPK cascade in both PH models which was abolished by sorafenib. In summary, sorafenib represents a novel potential treatment for severe PH with the MAPK cascade a potential canonical target.