We investigated the etiology of six problem behaviors that might facilitate an understanding of behavioral pathways to substance use and abuse in adolescents. These behavioral measures, classified as Conduct Problems, Hyperactivity, School Problems, Low Self-esteem, Neuroticism, and Social Withdrawal were the result of a previously reported (Siewert et al., 2003) modification of the Drug Use Screening Inventory (DUSI; Tarter, 1990; Tarter & Hegedus, 1991). We developed these measures as interpretable components of risk for substance use and abuse in a community based sample of 633 twin pairs, who were under the legal drinking age of 21 (mean age = 15.0 years). Using multivariate analyses, model comparisons indicated that these six behavioral measures could be thought of as two heritable, and genetically distinct, dimensions of problem behavior. Two closely competing models resulted from our analyses. The best fitting model hypothesized a general genetic factor loading on all 6 behavioral measures with a second genetic factor loading on only the three internalizing behavioral measures with loadings of 0.25–0.59 and 0.26–0.44, respectively. A second model, which fit the data almost as well, hypothesized one genetic factor loading only on the externalizing behavioral measures, and a second genetic factor loading only on the internalizing behavioral measures, with a correlation between the two latent factors of 0.75. Because our analyses show that there are two genetically distinct factors influencing these six problem behaviors, we anticipate that there may be different patterns of relationship of these factors to risk for substance use, abuse, and dependence.