In this study, the authors investigated the relation between reward and punishment sensitivity and adolescent substance use. The sample (N = 216; 130 girls, 85 boys) was drawn from high school and middle school students enrolled in a Midwestern suburban school district. Participants completed a substance use questionnaire and the Sensitivity to Punishment and Sensitivity to Reward Questionnaire (R. Torrubia, C. Avila, J. Molto, & X. Caseras, 2001). For 13 of 15 types of substance abuse, students with high reward sensitivity and low punishment sensitivity showed the highest levels of use. This finding supports the hypothesis of an interaction effect between reward sensitivity and punishment sensitivity and suggests that individuals who are high in reward sensitivity but low in sensitivity to punishment may be at a higher risk for substance abuse.