Hypoxia is more and more perceived as pivotal physiological driving force, allowing cells in the brain and elsewhere to acclimate to lowered oxygen (O ₂ ), and abridged metabolism. The mediating transcription program is induced by inspiratory hypoxia but also by intensive motor-cognitive tasks, provoking a relative decrease in O ₂ in relation to the acutely augmented requirement. We termed this fundamental, demand-dependent drop in O ₂ availability "functional hypoxia." Major players in the hypoxia response are hypoxia-inducible factors (HIFs) and associated prolyl-hydroxylases. HIFs are transcription factors, stabilized by low O ₂ accessibility, and control expression of a multitude of genes. Changes in oxygen, however, can also be sensed via other pathways, among them the thiol-oxidase (2-aminoethanethiol) dioxygenase. Considering the far-reaching biological response to hypoxia, hitherto mostly observed in rodents, we initiated a translational project, combining mild to moderate inspiratory with functional hypoxia. We had identified this combination earlier to benefit motor-cognitive attainment in mice. A total of 20 subjects were included: 13 healthy individuals and 7 patients with depression and/or autism spectrum disorder. Here, we show that motor-cognitive training under inspiratory hypoxia (12% O ₂ ) for 3.5 h daily over 3 weeks is optimally tolerated. We present first signals of beneficial effects on general well-being, cognitive performance, physical fitness and psychopathology. Erythropoietin in serum increases under hypoxia and flow cytometry analysis of blood reveals several immune cell types to be mildly modulated by hypoxia. To obtain reliable information regarding the "add-on" value of inspiratory on top of functional hypoxia, induced by motor-cognitive training, a single-blind study-with versus without inspiratory hypoxia-is essential and outlined here.