Maintenance of oxygen homeostasis is a fundamental physiological challenge. However the general operation of animal systems responding directly to oxygen availability was not appreciated until work on regulation the regulation of the erythropoietin gene led to the discovery of a system of direct oxygen sensing that operates in all animals. Post translational hydroxylation of specific prolyl and asparaginyl residues by a group of Fe(II) and 2-oxoglutarate (2-OG) dioxygenases directly couples the availability of oxygen to the regulation of HIF, the key transcription factor directing a very wide range of cellular and systemic responses to hypoxia. Co-factor requirements for Fe(II), ascorbate and 2-OG, as well as oxygen, potentially enable these enzymes to link biological responses to hypoxic, metabolic and redox stresses. The lecture will review the biochemistry, evolution and pan-genomic organization of the HIF hydroxylase pathways, and will address the wider role of intracellular protein hydroxylation in biological systems. It will also consider the implications of dysregulating large interconnected physiological pathways for cancer.