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Adapting to the developing relationship with their infants, parental brain systems coordinate contingent parent-infant behaviors to serve infant needs and create profound and far-reaching effects on infants. Parental brain circuits govern such parent-infant interactions in contexts of mental health as well as excess stress, socioeconomic disadvantage, and psychopathology across generations and cultures. In this review, biobehavioral mechanisms of risk and resilience are reviewed as targets for brain-based therapeutic interventions, and dialog among neurosciences, clinical experience, and the humanities.