This study investigates the role of hypoxia-inducible factor 1α (HIF-1α) in cellular and developmental oxygen homeostasis. HIF-1α is a key transcription factor that responds to low oxygen levels, regulating the expression of genes involved in glycolysis, angiogenesis, and other physiological processes. The authors generated Hif1a−/− embryonic stem (ES) cells and mice to investigate the effects of HIF-1α deficiency. They found that HIF-1α is essential for the normal expression of genes involved in glucose metabolism and angiogenesis, such as VEGF. In Hif1a−/− ES cells, the levels of mRNAs encoding glucose transporters and glycolytic enzymes were reduced, and cellular proliferation was impaired. In Hif1a−/− embryos, developmental arrest and lethality occurred by E11, with neural tube defects, cardiovascular malformations, and marked cell death in the cephalic mesenchyme. HIF-1α expression increased between E8.5 and E9.5 in Hif1a+/+ embryos, coinciding with the onset of developmental defects. These findings demonstrate that HIF-1α is a master regulator of cellular and developmental oxygen homeostasis, playing a crucial role in the formation and maintenance of physiological systems during embryonic development and postnatal life.This study investigates the role of hypoxia-inducible factor 1α (HIF-1α) in cellular and developmental oxygen homeostasis. HIF-1α is a key transcription factor that responds to low oxygen levels, regulating the expression of genes involved in glycolysis, angiogenesis, and other physiological processes. The authors generated Hif1a−/− embryonic stem (ES) cells and mice to investigate the effects of HIF-1α deficiency. They found that HIF-1α is essential for the normal expression of genes involved in glucose metabolism and angiogenesis, such as VEGF. In Hif1a−/− ES cells, the levels of mRNAs encoding glucose transporters and glycolytic enzymes were reduced, and cellular proliferation was impaired. In Hif1a−/− embryos, developmental arrest and lethality occurred by E11, with neural tube defects, cardiovascular malformations, and marked cell death in the cephalic mesenchyme. HIF-1α expression increased between E8.5 and E9.5 in Hif1a+/+ embryos, coinciding with the onset of developmental defects. These findings demonstrate that HIF-1α is a master regulator of cellular and developmental oxygen homeostasis, playing a crucial role in the formation and maintenance of physiological systems during embryonic development and postnatal life.