The article by M. Celeste Simon and Brian Keith discusses the role of oxygen availability in embryonic development and stem cell function. It highlights how low oxygen levels (hypoxia) naturally occur in developing embryos and how cells respond to these conditions by activating hypoxia-inducible factors (HIFs) and other molecules that regulate oxygen homeostasis. HIFs coordinate the development of various organs, including the blood, vasculature, placenta, and nervous system. Embryonic stem and progenitor cells often occupy hypoxic niches, and low oxygen levels regulate their differentiation. Recent studies have revealed a link between HIFs and factors involved in stem/progenitor cell behavior, providing a molecular framework for hypoxic control of differentiation and cell fate. The article also explores the implications of these findings for tissue regeneration and disease treatment. Key mechanisms discussed include the regulation of branching in tracheal development, cardiovascular morphogenesis, placentation, bone morphogenesis, and adipogenesis. Additionally, the article examines the context-dependent effects of oxygen levels on specific cell fates and the role of HIFs in maintaining stem cell quiescence, proliferation, and differentiation. The authors conclude that physiological hypoxia is essential for the development of all components of the cardiovascular-pulmonary system and that HIFs play a critical role in regulating stem cell behavior and function.The article by M. Celeste Simon and Brian Keith discusses the role of oxygen availability in embryonic development and stem cell function. It highlights how low oxygen levels (hypoxia) naturally occur in developing embryos and how cells respond to these conditions by activating hypoxia-inducible factors (HIFs) and other molecules that regulate oxygen homeostasis. HIFs coordinate the development of various organs, including the blood, vasculature, placenta, and nervous system. Embryonic stem and progenitor cells often occupy hypoxic niches, and low oxygen levels regulate their differentiation. Recent studies have revealed a link between HIFs and factors involved in stem/progenitor cell behavior, providing a molecular framework for hypoxic control of differentiation and cell fate. The article also explores the implications of these findings for tissue regeneration and disease treatment. Key mechanisms discussed include the regulation of branching in tracheal development, cardiovascular morphogenesis, placentation, bone morphogenesis, and adipogenesis. Additionally, the article examines the context-dependent effects of oxygen levels on specific cell fates and the role of HIFs in maintaining stem cell quiescence, proliferation, and differentiation. The authors conclude that physiological hypoxia is essential for the development of all components of the cardiovascular-pulmonary system and that HIFs play a critical role in regulating stem cell behavior and function.