The study of inherited disorders can provide significant insights into physiological processes. In keeping with this, recent genetic analyses of inherited erytrocytosis associated with disregulated erythropoietin (Epo) production have indicated an underlying defect in oxygen homeostasis. Phenotypically, these disorders generally manifest with a subtly raised haematocrit. When cells are well supplied with oxygen, the alpha subunit of the HIF transcription complex is proteasomally degraded, and Epo production is suppressed. This is achieved by the hydroxylation of key prolines in the oxygen degradation region of HIF-1a by a family of dioxygenases, PHD, and the subsequent degradation by the von Hippel-Lindau (VHL) E3 ubiquitin ligase complex. Although mutations in the VHL gene have been the major identified cause of erythrocytosis many cases remain unsolved. Screening the PHD family of enzymes in a group of such patients has detected a heterozygous P317R mutation in PHD2 and studying this variant has indicated that PHD2 is the key oxygen sensor.