Research suggests that genetic, prenatal, endocrine, and parenting influences across development individually contribute to internalizing and externalizing problems in children. The present study tests the contributions of genetic risk for psychopathology, prenatal maternal drug use and internalizing symptoms, child cortisol at age 4.5 years, and overreactive parenting influences across childhood together on 6-year-old children’s internalizing and externalizing problems. An adoption design was used that included 361 domestically adopted children and both biological and adopted parents prospectively followed from birth. Genetic and parenting influences contributed independently to externalizing, and that prenatal risk and cortisol did not mediate genetic or parenting influences on child externalizing problems. However, genetic and parenting factors were both directly and indirectly associated with internalizing problems (through increased prenatal risk and subsequent morning cortisol). Results suggest that prenatal and morning cortisol levels are mechanisms of genetic and environmental influences on internalizing problems, but not externalizing problems in childhood.