Since Joseph Priestley's demonstration in 1774 of the deleterious effects of a burning candle on a mouse in a bell jar, we have known that oxygen is essential for animal life. Only recently, however, have we begun to understand how animal cells sense when oxygen is limiting and respond to the crisis of hypoxia. Cellular responses range from rapid changes in carbohydrate metabolism to permanent restructuring of their blood supply. Remarkably, studies of these diverse phenomena have recently converged on a common pathway employed by cells to sense hypoxia and activate specific genes to deal with the crisis. Not only is this pathway crucial for normal tissue physiology, but its failure can contribute to diseases such as myocardial infarction and anemia, and its misregulation can lead to retinopathy and tumor growth. Here we describe the recent advances in the molecular response to hypoxia and the identification of the HIF-1 transcription factor as a central component in the hypoxic response pathway.