Although O(2) concentrations are considerably lowered in vivo, depending on the tissue and cell population in question (some cells need almost anoxic environment for their maintenance) the cell and tissue cultures are usually performed at atmospheric O(2) concentration (20-21%). As an instructive example, the relationship between stem cells and micro-environmental/culture oxygenation has been recapitulated. The basic principle of stem cell biology, "the generation-age hypothesis," and hypoxic metabolic properties of stem cells are considered in the context of the oxygen-dependent evolution of life and its transposition to ontogenesis and development. A hypothesis relating the self-renewal with the anaerobic and hypoxic metabolic properties of stem cells and the actual O(2) availability is elaborated ("oxygen stem cell paradigm"). Many examples demonstrated that the cellular response is substantially different at atmospheric O(2) concentration when compared to lower O(2) concentrations which better approximate the physiologic situation. These lower O(2) concentrations, traditionally called "hypoxia" represent, in fact, an in situ normoxia, and should be used in experimentation to get an insight of the real cell/cytokine physiology. The revision of our knowledge on cell/cytokine physiology, which has been acquired ex vivo at non physiological atmospheric (20-21%) O(2) concentrations representing a hyperoxic state for most primate cells, has thus become imperious.