<p>Despite extensive research, brain lateralization remains theoretically fragmented, especially regarding the functional integration of hemispheric asymmetries, bilateral contributions to cognition, and the significance of lateralization degree for development and clinical practice. This fragmentation is reflected in often contradictory findings across various domains such as language, social cognition, creativity, and psychopathology. To address these challenges, this paper offers theoretical and methodological reinterpretations of lateralization grounded in Cultural-Historical Activity Theory (CHAT). Building on the law of extracortical organization of the brain, we argue that hemispheric specialization largely reflects the intracerebral manifestation of a dual organization of internal psychological activity, by emphasizing self-realization and alienation in the social structure. Specifically, we conceptualize internal activity as two interrelated yet non-coinciding spheres: a self (unconscious personality)-relevant sphere of meaning emergence, and an “I” (conscious personality)-relevant sphere of personal sense-making. By mapping CHAT principles onto lateralization findings—including bilateral language involvement, creativity, and links between lateralization-degree and psychopathology—we propose that these dual activities are associated with the cerebral hemispheres, with the right hemisphere preferentially supporting self-relevant and unconscious meaning-related processes, and the left hemisphere supporting language-mediated, hierarchical, and consciously regulated sense-making. More broadly, our proposed framework contributes to ongoing efforts to address reductionism and fragmentation in psychology and neuropsychology. We conclude by outlining implications for developmental, clinical, and neuropsychological research, and propose empirically testable directions for future studies.</p>