Shelter-recruited adolescents are known to have high rates of substance abuse and co-occurring internalizing and externalizing problem behaviors. Many studies have documented these mental health concerns, but only a small number of studies have tested interventions that may be useful for ameliorating these vulnerabilities. The current study compared three empirically supported psychotherapy interventions, Motivational Interviewing (MI), the Community Reinforcement Approach (CRA), and Ecologically-Based Family Therapy (EBFT) with 179 substance abusing runaway adolescents (47% female, 74% minority) and their primary caretaker recruited through a Midwestern runaway crisis shelter. Examining both child and primary caretaker reports, each treatment was associated with significant reductions in internalizing and externalizing behaviors to 24 months post-baseline. However, the trajectory of change differed among the treatments. Adolescents receiving MI showed a quicker reduction in internalizing and externalizing behaviors but also a quicker increase in these behaviors compared to adolescents receiving EBFT, who continued to evidence improvements to 24 months. The findings provide support for continued evaluation of these treatments for use with this vulnerable population of adolescents.