This article summarizes the 30+-year evidence base of Multidimensional Family Therapy (MDFT), a comprehensive treatment for youth substance abuse and antisocial behaviors. Findings from four types of MDFT studies are discussed: hybrid efficacy/effectiveness randomized controlled trials, therapy process studies, cost analyses, and implementation trials. This research has evaluated various versions of MDFT. These studies have systematically tested adaptations of MDFT for diverse treatment settings in different care sectors (mental health, substance abuse, juvenile justice, and child welfare), as well as adaptations according to treatment delivery features and client impairment level, including adolescents presenting with multiple psychiatric diagnoses. Many published scientific reviews, including meta-analyses, national and international government publications, and evidence-based treatment registries, offer consistent conclusions about the clinical effectiveness of MDFT compared with standard services as well as active treatments. The diverse and continuing MDFT research, the favorable, multi-source independent evaluations, combined with the documented receptivity of youth, parents, community-based clinicians and administrators, and national and international MDFT training programs (U.S.-based organization is MDFT International, www.mdft.org; and Europe-based organization is www.mdft.nl) all support the potential for continued transfer of MDFT to real-world clinical settings.