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Puberty is characterized by a large number of physiological modifications that translate into increased neuromuscular fatigue during high-intensity exercise in adolescents compared to prepubertal children. This greater neuromuscular fatigue in adolescents could be attributed to peripheral (i.e., muscular) and central (i.e., nervous) factors that change through puberty. Among the peripheral changes are muscle mass, fiber type composition, energy metabolism and musculo-tendinous stiffness. Among the central modifications are the voluntary activation level, the antagonist co-activation and a differential interplay between central and peripheral fatigue. The objective of this review article will be to underline the importance of these factors on the development of neuromuscular fatigue during high-intensity exercise throughout puberty and to highlight that the adolescents could be physiologically less protected against fatiguing high-intensity exercise than their prepubertal counterparts.