Development involves synergistic interplay among genotypes and the physical and cultural environments, and integrating genetics into experimental designs that manipulate the environment can improve understanding of developmental psychopathology and intervention efficacy. Consistent with differential susceptibility theory, individuals can vary in their sensitivity to environmental conditions including intervention for reasons including their genotype. As a consequence, understanding genetic influences on intervention response is critical. Empirically, we tested an interaction between a genetic index representing sensitivity to the environment and the Family Check-Up intervention. Participants were drawn from the Early Steps Multisite randomized prevention trial that included a low-income and racially/ethnically diverse sample of children and their families followed longitudinally (n = 515). As hypothesized, polygenic sensitivity to the environment moderated the effects of the intervention on 10-year-old children's symptoms of internalizing psychopathology, such that children who were genetically sensitive and were randomly assigned to the intervention had fewer symptoms of child psychopathology than genetically sensitive children assigned to the control condition. A significant difference in internalizing symptoms assessed with a clinical interview emerged between the intervention and control groups for those 0.493 SD above the mean on polygenic sensitivity, or 25% of the sample. Similar to personalized medicine, it is time to understand individual and sociocultural differences in treatment response and individualize psychosocial interventions to reduce the burden of child psychopathology and maximize well-being for children growing up in a wide range of physical environments and cultures.