This study examines interactions of heritable influences, prenatal substance use, and postnatal parental warmth and hostility on the development of conduct problems in middle childhood for boys and girls. Participants are 561 linked families, collected in 2 cohorts, including birth parents, adoptive parents, and adopted children. Heritable influences on internalizing and externalizing (including substance use) problems were derived from birth mothers' and fathers' symptoms, diagnoses, and age of onset from diagnostic interviews, and the proportion of first-degree relatives with the same type of problems. Smoking during pregnancy (SDP) and alcohol use during pregnancy were assessed retrospectively from birth mothers at 5 months postpartum. Earlier externalizing problems and parental warmth and hostility and were assessed at 1 assessment prior to the outcome (Cohort II: 4.5 years; Cohort I: 7 years). Conduct problems were symptoms from a diagnostic interview assessed at age 6 (Cohort II) or 8 (Cohort I). Findings from regression analyses suggest that (a) SDP plays an important role for the development of conduct problems, (b) some relatively well-accepted effects (e.g., parental hostility) were less important when simultaneously considering multiple factors influencing the development of conduct problems, and (c) main effects of genetic risk and SDP, and interactions among genetic risk and postnatal warmth, SDP and postnatal warmth, and genetic risk, SDP, and postnatal hostility for conduct problems were important for boys' but not girls' conduct problems. Replication is needed, but the current results provide preliminary but empirically grounded hypotheses for future research testing complex developmental models of conduct problems.