There is a limited understanding as to how specific genes impact addiction risk. Applying a developmental framework and research domain criteria (RDoC) to identify etiological pathways from genetic markers to addiction may have utility. Prior research has largely focused on externalizing pathways to substance use. Although internalizing mechanisms have received less attention, there is strong support that addiction is a longer term consequence of using substances to cope with internalizing as well as externalizing problems. This study tests whether temperament and depression mediate the association between specific genetic variants and substance use. The sample consisted of 426 adolescents from the Michigan Longitudinal Study (70.9% boys, 84.0% White). Four specific genetic variants were examined: SLC6A4 (5HTTLPR), BDNF (rs6265), NPY (rs3037354), and CRHBP (rs7728378). Childhood resiliency and behavioral control were examined as potential mediators, in addition to early adolescent depression, using a multiple-mediator path model. Resiliency and depression were supported as mediators in the association between genetic risk and later substance use. Important differences emerged across substances of abuse. Indirect effects via depression were not significant with the inclusion of aggression. Early difficulties with emotional coping may represent nonspecific neurobiological underpinnings for an internalizing pathway to addiction.