The ability to sense and respond to changes in oxygen concentration is a fundamental requirement for the survival of all organisms. Throughout evolution, control of oxygen homeostasis has developed into a complex system, requiring both rapid adjustment to acute changes in oxygen and durable adaptation when the hypoxic stimulus is prolonged. There are numerous instances, in both physiologic and pathophysiologic conditions, during which the lung experiences localized or global hypoxia. It has become increasingly appreciated that adaptation to hypoxia requires the coordinated regulation of a large battery of genes, and that this collective response is controlled, to a large extent, at the level of transcription. In particular, the hypoxia-inducible factors (HIFs), have been identified as key mediators of adaptation to hypoxia. In this review, we will describe the HIF system and its role in a variety of developmental, physiologic, and pathogenic processes within the lung.