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This review presents the mechanisms for the development of fatigue associated with psychophysical overload. The aim of the work was the analysis of available literature sources touching upon the problem of psychophysical fati-guability. This study was conducted using information retrieval systems (PubMed), as well as databases (eLibrary). Physical exertion experienced by highly skilled athletes, as well as persons in hazardous occupations (divers, astronauts, alpinists), leads to the activation of free radical reactions, CNS disorders, metabolic disorders, oxidative stress, and mitochondrial dysfunctions, which lead to the development of many different diseases and reduced labor activity. It has been established that the pathogenesis of psychophysical fatigue combines psychomental and musculoskeletal symptoms, by acting upon which, it is possible to reduce the manifestations of fatigue. The analysis of various publica-tions made it possible to establish the key elements of the pathogenesis of this dysfunction with possible ways of its pharmacological correction. Key words: psychophysical fatigue, highly skilled athletes, actoprotectors, oxidative stress, mitochondrial dysfunction, apoptosis, Metaprot.