<p>Recent evidence challenged the traditional, categorical approach to sex differences, indicating that each human brain comprises a mosaic of features, some of which are more common among males, others, among females, whereas the remaining are equally common between sexes. Thus, a focus on regional sexual differentiation of brain function, instead of holistic sex-based categorization, could be more useful for understanding psychiatric conditions, such as mood and behavioural disorders, to which males and females are differentially vulnerable. To probe this untested hypothesis, we estimate sexual differentiation within each brain in a longitudinal (<i>N</i> = 199) and cross-sectional (<i>N</i> = 277) sample of male and female adolescents. Greater feminization of association networks, involved in higher-order cognition, compared to sensory networks, at ages 9-10 correlates with earlier puberty and greater immune/metabolic dysregulation at ages 11-12, particularly among girls. Greater masculinization of association networks relates to later puberty and reduced immune/metabolic dysregulation, especially among boys. The brain and physiological profiles sequentially mediate the relationship between genetic risk and rising mood/behavioural symptoms. These links are replicated in the cross-sectional sample and shown to hold across sexes. Our study emphasizes the importance of integrating assessments of regional sexual differentiation and physiology in personalizing psychiatric intervention in adolescence.</p>