Metazoan life is dependent upon the utilization of O(2) for essential metabolic processes and oxygen homeostasis is an organizing principle for understanding metazoan evolution, ontology, physiology, and pathology. Hypoxia-inducible factor 1 (HIF-1) is a transcription factor that is expressed by all metazoan species and functions as a master regulator of oxygen homeostasis. Recent studies have elucidated complex mechanisms by which HIF-1 activity is regulated and by which HIF-1 regulates gene expression, with profound consequences for prenatal development, postnatal physiology, and disease pathogenesis.