Through randomized clinical trials, Multisystemic Therapy (MST) has been identified as an effective treatment of youth antisocial behavior, including substance abuse. The evidence base for MST spans the past two decades. Youths in MST treatment conditions, in comparison with counterparts receiving alternative services, have demonstrated reduced substance use, decreased criminal activity, improved mental health symptoms, increased school attendance, and reduced rates of out-of-home placement. In light of these favorable outcomes, research attention has begun to focus on testing strategies for further enhancing the effectiveness of MST in treating substance abuse and on determining the conditions needed for the effective transport of MST and other evidence-based treatments. The MST assessment process and intervention protocols focus on individual, family, peer, school, and social network variables that are linked with identified problems, as well as on the interface of these systems. The MST model, focusing on youths with serious antisocial behavior who are at imminent risk of costly out-of-home placements and their families, was shaped by general systems theory and theory of social ecology. Focusing on its implementation with alcohol and other drug using adolescents, this paper offers an overview of the clinical applications of MST and summarizes findings from clinical trials using MST to treat substance use disorders in adolescents. References, figure