This study examines interactions of heritable influences, prenatal substance use, and postnatal environmental influences on the development of conduct problems in middle childhood for boys and girls. Participants are 561 linked families, collected in two 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 post-partum. Earlier externalizing problems and parental warmth and hostility and were assessed at one 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 1) SDP plays an important role for the development of conduct problems, 2) some relatively well-accepted effects (e.g., gene × SDP interactions) were less important when considering a fuller picture of the development of conduct problems in this sample, and 3) there were sex differences in main effects and interactions among genetic, prenatal substance use, and postnatal (parenting) influences on conduct problems that may be important to consider in future work. Replication is needed, but the current results provide preliminary but empirically-grounded hypotheses for future research testing complex developmental models of conduct problems.