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Movement as a Neuromodulator: How Physical Activity Influences the Physiology of Adolescent Depression Abstract: In the context of adolescent depression, physical activity is becoming increasingly recognized for its positive effects on neuropathology. Current scientific findings indicate that physical training affects the biological effects of depression during adolescence. Yet the pathophysiology of adolescent depression is not yet fully understood. Besides psychosocial and genetic influences, various neurobiological factors are being discussed. One explanation model describes a dysfunction of the hypothalamus-pituitary-adrenal axis (HPA axis) with a sustained elevation in cortisol concentration. Recent studies highlight neuroimmunological processes and a reduced concentration of growth factors as causative factors. These changes appear to lead to a dysregulation of the excitation and inhibition balance of the cerebral cortex as well as to cerebral morphological alterations. Regular physical training can potentially counteract the dysregulation of the HPA axis and normalize cortisol levels. The release of proinflammatory cytokines is inhibited, and the expression of growth factors involved in adult neurogenesis is stimulated. One should ensure the synergistic interaction of biological and psychosocial factors when designing the exercise schedule (endurance or strength training, group or individual sports, frequency, duration, and intensity). Addressing these open questions is essential when integrating physical activity into the guidelines for treating depressive disorders in children and adolescents.