Purpose To examine stress reactivity in a sample of prenatally drug exposed (PDE) adolescents by examining the consequences of PDE on stress-related adrenocortical reactivity, behavioral problems and drug experimentation during adolescence. Methods Participants (76 PDE, 61 non-drug exposed [NE]; 99% African-American; 50% male; Mage=14.17 years, SD=1.17) provided a urine sample, completed a drug use questionnaire, and provided saliva samples (later assayed for cortisol) before and after a mild laboratory stress task. Caregivers completed the Behavior Assessment System for Children II and reported their relationship to the adolescent. Results The NE group was more likely to exhibit task-related cortisol reactivity, compared to the PDE group. Overall behavior problems and drug experimentation were comparable across groups with no differences between PDE and NE groups. In unadjusted mediation analyses, cortisol reactivity mediated the association between PDE and BASC II aggression scores (95% bootstrap CI: 0.04-4.28), externalizing problems scores (95% bootstrap CI: 0.03-4.50) and drug experimentation (95% bootstrap CI: 0.001-0.54). The associations remain with the inclusion of gender as a covariate but not when age is included. Conclusions Findings support and expand current research in cortisol reactivity and PDE by demonstrating that cortisol reactivity attenuates the association between PDE and behavioral problems (aggression) and drug experimentation. If replicated, prenatal drug exposure may have long lasting effects on stress-sensitive physiological mechanisms associated with behavioral problems (aggression) and drug experimentation in adolescence.