All organisms can sense O-2 concentration and respond to hypoxia with adapt
ive changes in gene expression. The large body size of mammals necessitates
the development of multiple complex physiological systems to ensure adequa
te O-2 delivery to all cells under normal conditions. The transcriptional r
egulator hypoxia-inducible factor 1 (HIF-1) is an essential mediator of O-2
homeostasis. HIF-1 is required for the establishment of key physiological
systems during development and their subsequent utilization in fetal and po
stnatal life. HIF-1 also appears to play a key role in the pathophysiology
of cancer, cardiovascular disease, and chronic lung disease, which represen
t the major causes of mortality among industrialized societies. Genetic or
pharmacological modulation of HIF-1 activity in vivo may represent a novel
therapeutic approach to these disorders.