Photosynthesising cyanobacteria breathed life into what was, until a billion years ago considered a reductive atmosphere, thus providing a selective pressure for the evolution of (oxygen) O2-dependent micro-organisms that began with the autotrophic eukaryotes. Since these primordial times, the respiring mammalian cell has become entirely dependent on molecular O2 since it serves as the terminal electron acceptor in mitochondrial oxidative phosphorylation and multiple enzymes require O2 as a substrate. The human brain exemplifies this reliance on O2 since, unlike most other tissues, an evolutionary “drive for size” means that it is now committed to a continually active state. However, this comes at a cost and corresponding high vulnerability for failure. Given that the brain’s O2 supply is so delicate, it would seem likely that evolution has favoured a feedback mechanism that senses tissue PO2 and consequently transmits a signal to the vasculature coupling local O2 delivery to tissue metabolic demand. The current presentation will combine the joys of laboratory-based science with the thrills (and dangers!) of extreme field testing to shed unique insight into fundamental molecular mechanisms that allows the human brain to sense O2 and the mechanisms that regulate its delivery. Experiments with “super-human” models including high-altitude mountaineers and freedivers will be discussed, providing unique insight into how our brains can adapt and overcome extremes of O2-lack that would otherwise be considered incompatible with ordinary human life.