Transdisciplinary scientific collaborations (TDSCs) have the potential to strengthen substance use and misuse research and prevention. Despite its growing prominence as a mode for scientific research, research on TDSC remains in a nascent form and its value to the field of substance use and misuse merits further exploration. The overarching purpose of this article is to examine the potential contributions of transdisciplinary science to research and prevention using conceptualizations, methods, and evidence from a case study of two university-based research centers. The article provides (a) a discussion of the societal context and historical developments that have prompted increasing interest in TDSC; (b) a definition and conceptualization of TDSC; (c) a methodological approach for studying TDSC; (d) initial findings from the case study that reflect instances of transdisciplinary intellectual integration and it examines implications of these methods and findings for future research and policy development relevant to substance use and misuse.