Large life, as currently present on Earth, diversified during a late and seemingly non-trivial historic event. Although other biological revolutions – such as the advent of photosynthesis or the eukaryotic cell – are attributed to innovations within life itself, the dramatic diversification of animals tends to associated with a change in the environment. The environmental change that remains most thoroughly explored and debated is that of a synchronous increase of free oxygen. Paradoxically, studies of multicellularity from the perspective of tissue and of successful tumor growth highlight how oxic settings are incompatible with the core mechanism of tissue renewal (Ivanovic, 2009). Tumor biology also demonstrates biological mechanisms that, through the hypoxia inducible transcription factors (HIFs), overcome this paradox (Pietras et al., 2008) and, thus, allow tissue renewal despite oxic settings. We have explored how HIFs may serve as an adaption within multicellularity that allow viable large life forms in the oxic setting, by offering improved control of the cellular hypoxia-response machinery that sustain oxygen-insensitive growth of complex tissue. We found that this control is animal-specific and is at its highest refinement within vertebrate animals; in which the innovation of high-oxygen carrying capacity through red blood cells followed first subsequently (Hammarlund et al., 2018). We hypothesize that such a refinement within biology itself, during the Neoproterozoic, allowed metazoans to fully access and exploit the primordial oxic niche on Earth. Testable predictions of this perspective, such as that invertebrate animals and other large multicellular organisms still require phases or settings of truly hypoxic conditions to manage tissue renewal, have implications that reach from geology and medicine to astrobiology. Indeed, a perspective based in the prerequisites of tissue maintenance suggests that being large is a biological achievement of cosmic proportions.