Oxygen occupies a central role in the maintenance of life as we know it, perhaps most prominently in aerobic metabolism, where O2 serves as the terminal electron acceptor in oxidative phosphorylation. However, oxygen transport by simple diffusion becomes limiting as organisms become larger and more active. To maintain oxygen homeostasis, higher eukaryotes have adopted specialized mechanisms to enhance O2 uptake and distribution. The resulting respiratory and circulatory systems are dynamic, capable of responding to changes in oxygen availability on either a local or organismal level. Though some oxygen-dependent responses rely on the activity of specialized oxygen-sensing cells, conserved oxygen-responsive pathways are expressed in almost every mammalian cell. In fact, this ability of individual cells to sense and respond to changes in oxygen availability is critical for many developmental, physiological, and pathological processes. Unlike the rapid responses to changes in oxygen availability, which can be mediated through posttranslational modifications or membrane depolarization (for review, see López-Barneo et al. 2001), this ubiquitous hypoxic response pathway involves changes in gene expression that occur over several hours. These changes are mediated in part through the induction of hypoxia-inducible transcription factors, the regulatory components of which can also be found in simpler eukaryotes such as fruit flies and nematodes.