The current study proposed that empathy may indirectly play a protective role for adolescents in drug use behaviors and that this relationship will be mediated by self-regulatory strategies found in drug refusal efficacy. We predict that empathy will be linked to prosocial behavior and aggression, though we do not believe that they will mediate the relationship between empathy and drug use. The sample included 498 African-American adolescents in the 6th, 7th, and 8th grade. The results of structural equation modeling provided support for our hypotheses. Empathy was significantly and positively associated with drug refusal efficacy and prosocial behavior. Empathy was negatively associated with aggression. Drug refusal efficacy was negatively related to past 30-day drug use, providing evidence for the fully mediating role of drug refusal self-efficacy on empathy and past 30-day drug use. Consistent with our predictions, aggression and prosocial behavior were not significantly associated with past 30-day drug use. These findings may be useful in the context of programming efforts for drug prevention. (Contains 2 tables and 2 figures.)