Hypoxia is increasingly seen as urgent physiological driving force, permitting cells within the brain and in other parts of the body to acclimate to lowered oxygen (O2) and reduced metabolism. The mediating transcription program is induced by inspiratory hypoxia but also by intensive motor-cognitive tasks, provoking a relative decrease in O2 in relation to the acutely augmented requirement. We named this essential, demand-dependent drop in O2 accessibility ′functional hypoxia′. Major players within the hypoxia reaction are hypoxia-inducible factors (HIF) and associated prolyl-hydroxylases. HIF are transcription factors, stabilized by low O2 availability, and control expression of a large number of genes. Considering the far-reaching natural reaction to hypoxia, until now generally watched in rodents, we initiated a translational approach, combining mild to moderate inspiratory with functional hypoxia. We had identified this combination prior to enhance motor-cognitive achievement in mice. In total 20 subjects were included, 13 healthy individuals and 7 patients with depression and/or autism spectrum disorders. We show that motor-cognitive training under inspiratory hypoxia (12% O2) for 3.5 hours over 3 weeks is well 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 planned.