Mammals sense low pO2 (hypoxia) by processes over multiple length scales, ranging from cellular-based pathways up through tissue-based pathways. The most prominent O2-sensing pathway centres on the hypoxia inducible factor (HIF), which induces gene expression under hypoxic conditions. HIF is regulated primarily by the HIF hydroxylases, the factor inhibiting HIF (FIH) and prolyl hydroxylase domain (PHD) enzymes, which are nonhaem Fe, alpha-ketoglutarate dependent dioxygenases. FIH and PHD recognize selective sequences on HIFα, but they also hydroxylate alternative substrates, such as proteins containing ankyrin repeat domains (ARDs) and a variety of proteins involved in cellular stress responses. Consequently, the search for new substrates of FIH and PHD is a rich area of research. Proposals for additional O2 sensors, such as H2S and the F-box and leucine-rich repeat protein 5 (FBXL5), are introduced. The tissue-level responses of vasopermeation and vasoconstriction are discussed, and connected to cellular events such as changes in potassium channels.