In the 1980s a model of adaptive and pathologic responses to acute and chronic hypoxia was described in which Madison (M) rats had pathologic response to acute hypoxia (development of i.e. pulmonary edema) and adaptive responses to chronic hypoxia, where as in contrast, Hilltop (H) rats adapted well to acute but not chronic hypoxia (development of pulmonary edema and hypertension as well as widespread vascular remodelling). The transcription factor Hypoxia-inducible factor-1 (HIF-1) has been extensively investigated and its role as a protective factor has been clearly established. Also, it was indicated that M rats had lower HIF-1 activity compared to H rats under hypoxia. Thus, we utilized this model to hypothesize that protection from acute hypoxia was associated with elevated HIF-1 activity whereas a prolonged HIF-1 activation would lead to a pathologic response. Cardiopulmonary hemodynamics, blood gasses, right ventricular hypertrophy and pulmonary leak, vascular remodelling, HIF-1 DNA- binding and plasma Epo and VEGF were determined in these animals under acute (24h) or chronic (21d) hypoxic (18,000ft/5500m) or normoxic conditions. Pulmonary HIF-1 DNA-binding activity was unchanged in acute and chronic hypoxia-exposed M rats, but elevated in H rats. We conclude that pulmonary HIF-1 DNA-binding activity is associated with protection from acute hypoxia, while prolonged activity is associated with pathologic response to chronic hypoxia.