Objective: To produce a theoretical approach about the relations between neuroscience and psychopathology that expands beyond the biomedical model to include a non-reductionist, enactive, and biocultural perspective. Method: An integrative review, drawing from the biocultural approach from Anthropology, is used to produce examples from epigenetics, neuroplasticity, and functional neuroanatomy. Results and conclusion: A biocultural approach points to a brain that is highly plastic, reinforcing a much more complex model in which biological vulnerabilities and the historical-cultural environment co-construct each other. The examples given seem to point to the pressing need for a critical expansion of reductionist models of psychopathology. Importantly, the cultural-historical environment to which we refer is not a set of neutral social relations to which individuals are homogeneously exposed, such that aspects that are usually studied under the social determinants of health and disease (poverty, discrimination, violence, and other factors that represent sources of control, production, and distribution of material resources, ideology, and power) need to be incorporated in adequate biopsychosocial models of mental distress.