Molecular oxygen (O2)is a basic requirement for cellular growth and viability and many aspects of anatomy and physiology are dedicated to achieving reliable distribution. Recent work has identified a specific sensing and response system, centred around a transcription complex called Hypoxia-inducible Factor 1 (HIF-1), which forms the focus of this review. The HIF-system operates in all cell types and modulates a very broad range of cellular pathways, consistent with the broad importance of oxygen. It is implicated in a rapidly expanding range of developmental, physiological and pathological settings, and is potentially relevant to almost all areas of clinical medicine. Excitingly, the pathway can be activated with low molecular weight compounds which should offer therapeutic benefit, especially in diseases where oxygen supply is compromised.