During adolescence there is a significant increase in risk-taking behavior, including experimenting with alcohol and drugs, which can lead to drug dependence. A new hypothesis regarding the genetic mechanisms that lead to drug use is tested using adolescent Caucasian children of alcoholics (57 males, 54 females; mean age = 14.5 years) data. Variables included in the study were dopaminergic genes (ANKK1 TaqI A, DRD2 C957T, DRD4 7R, COMT Val/Met substitution, and SLC6A3 9R) and a GABAergic gene (GABRB3), all combinations of genes, a count of the number of hypodopaminergic genotypes, personality traits, neurocognitive factors, depressive symptoms, and environmental factors. Separate predictive models were found for males and females. Hypodopaminergic functioning predicted drug use in males; however, in females, a deleterious environment was the salient predictor. This preliminary study suggests that it is possible to identify children at risk for problematic drug use prior to the onset of drug dependence. © 2010 Elsevier Inc. All rights reserved.