Rationale. Pulmonary hypertension is a common complication of chronic hypoxic lung diseases and is associated with increased morbidity and reduced survival. The pulmonary vascular changes in response to hypoxia, both structural and functional, are unique to this circulation. Objective. To identify transcription factor pathways uniquely activated in the lung in response to hypoxia. Methods. Following exposure to environmental hypoxia (10% O2) for varying periods (3 hours to 2 weeks), lungs and systemic organs were isolated from groups of adult male mice. Bioinformatic examination of genes whose expression changed in the hypoxic lung (assessed using microarray analysis) identified potential lung selective transcription factors controlling these changes in gene expression. In separate further experiments, lung-selective activation of these candidate transcription factors was tested in hypoxic mice and by comparing hypoxic responses of primary human pulmonary and cardiac microvascular endothelial cells in vitro. Measurements and Main Results. Bioinformatic analysis identified CREB family members as candidate lung selective hypoxia responsive transcription factors. Further in vivo experiments demonstrated activation of CREB and ATF1 and upregulation of CREB family responsive genes in the hypoxic lung but not in other organs. Hypoxia dependent CREB activation and CREB responsive gene expression was observed in human primary lung but not cardiac microvascular endothelial cells. Conclusions. These findings suggest that activation of CREB and AFT1 plays a key role in the lung-specific responses to hypoxia and that lung microvascular endothelial cells are important, proximal effector cells in the specific responses of the pulmonary circulation to hypoxia.