Mammalian cells sense changes in oxygen and transduce that information into adaptive changes in gene expression using a conserved pathway that converges on the heterodimeric transcription factor called hypoxia-inducible factor (HIF), which contains a labile alpha subunit and a stable beta subunit. In the presence of oxygen, the alpha subunit is hydroxylated on one (or both) of two highly conserved prolyl residues by an Egg-Laying Defective Nine (EglN)[also called Prolyl Hydroxylase Domain (PHD)] dioxygenase, which recruits an ubiquitin ligase complex containing the VHL tumor suppressor gene product. Germline VHL mutations cause von Hippel-Lindau (VHL) disease, which manifest as angiogenic tumors such as hemangioblastomas and kidney cancers. Somatic VHL inactivation and deregulation of HIF (especially HIF2α) drives sporadic kidney cancers and an HIF2α inhibitor is showing promise for this disease. VHL, EglN1, and HIF2α polymorphisms have been linked to familial polycythemia and adaptation to high altitude. Orally available EglN inhibitors are being developed for the treatment of anemia and ischemic diseases.