Significance: We undertook an interdisciplinary exploration that unites evolutionary biology, neuroscience, and developmental cultural psychology. Based on extensive and detailed behavioral analyses of 684 new mothers in 11 countries and complementary functional magnetic resonance imaging (fMRI) analyses of brain responses in 43 first-time new US mothers to their own infants’ cries, 44 experienced Chinese mothers to infant cries and control emotional sounds, and 12 Italian mothers and nonmothers to generic infant cries, we identified specific behavior repertoires and specific corresponding activated brain regions in human caregivers that constitute primary responses to infant distress. This study set will appeal to scientific and general audiences because it elucidates the foundations of core parenting practices in response to infant vocal distress.