IN HUMANS AND OTHER mammals, decreased oxygen tension triggers specific and tightly regulated cellular, vascular, and erythropoietic responses. An association between polycythemia and people living at high altitudes was first reported in 1863. 1 Erythropoietin (Epo), a 34.4-kD glycoprotein hormone, was subsequently identified as the humoral regulator of red blood cell production. Decreased tissue oxygen tension modulates Epo levels by increasing expression of the Epo gene. Since the cloning of the Epo gene in 1985, 2, 3 considerable progress has been made in understanding the molecular mechanisms by which the Epo gene is regulated by environmental, tissue-specific, and developmental cues. Erythropoiesis, which normally proceeds at a low basal level to replace aged red blood cells, is highly induced by loss of red blood cells, decreased ambient oxygen tension, increased oxygen affinity for hemoglobin, and other stimuli that decrease delivery of oxygen to the tissues. In states of severe hypoxia, production of Epo is increased up to 1,000-fold. The secreted hormone circulates in the blood and binds to receptors expressed specifically on erythroid progenitor cells, thereby promoting the viability, proliferation, and terminal differentiation of erythroid precursors, resulting in an increase in red blood cell mass. The oxygen carrying capacity of the blood is thus enhanced, increasing tissue oxygen tension, thereby completing the negative feedback loop (Fig 1). 4, 5 Research on the regulation of the Epo gene has shown a general system of oxygen-sensing, signaling, and transcriptional regulation of a broad range of physiologically relevant genes, including those encoding angiogenic growth factors, glucose transporters, and enzymes involved in adaptation to hypoxia.