Scientists date the “Big Bang” to about 13.8 billion years ago.The solar system was dated at about 4.5-4.6 billion years ago forming the central star, the Sun, and orbiting planets. Planet Earth is unique because it has about 70% of its surface covered with water and is nestled at just the right distance from the Sun for water to be in liquid form and not to evaporate. The primitive atmosphere of the Earth did not contain Oxygen. For about 1 billion years there were not life forms of any type on Earth. The fossil record and genetic evidence suggest that prokaryotic cells were the first organisms on Earth, like cyanobacteria. At 3.5 billion years ago primitive cyanobacteria started releasing massive amounts of Oxygen through photosynthetic reactions trasforming the atmospheric CO2 with the energy from the Sun. Then, at around 2 billion years ago Oxygen began to building up on Earth’s atmosphere and proved to be the critically defining element for the transition from anaerobic organisms to the development of aerobic multicellular eukaryotic life on Earth. Animals need Oxygen for the conversion of food into useful energy. The endosymbiotic theory resolved the “mystery” of evolutionary processs that promoted the formation of eukaryotes from prokaryotic cells evolving together over time. Mitochondria in eukaryotic cells played an important role and often are called the “energy factories”, responsible for making Adenosine Triphosphate (ATP). The fundamental importance of Oxygen has been understood for centuries, but how eukariotic cells adapt to changes in levels of Oxygen has long been unknown. The seminal discoveries of 2019 year’s Nobel Prize laureates for Physiology or Medicine revealed the mechanism for one of life’s most essential adaptive processes of how Oxygen levels affect cellular metabolism and physiological function in biological organisms. Scientific research proved that hypoxia-inducible factors (HIFs) are transcriptional activators that function as master regulators of Oxygen homeostasis in all metazoan species (animal and plants). Rapid progress is being made in elucidating homeostatic roles of HIFs in many physiological systems, determining pathological consequences of HIF dysregulation in chronic diseases, and investigating potential targeting of HIFs for therapeutic purposes. This review collected the most important scientific papers and dedicated research on the subject of Oxygen regulation in aerobic multicellular organisms through the hypoxia-inducible factors. Years of research lead to the discovery of the molecular machinery that allows cells to sense and respond to changes in oxygen levels and availability.