Despite research and intervention efforts, the abuse and misuse of substances remains a serious problem in the United States. Recently, growing attention has been focused on TDSC as a model for scientific research in the field of substance misuse. The current article seeks to examine the potential contributions TDSC can make to the substance abuse field through a case study of two university-based substance use research centers, the Transdisciplinary Tobacco Use Research Centers. The case studies were of the University of California, Irvine TDSC and the University of Southern California TDSC; interviews and behavioral observations were conducted with staff and administrators, and researchers. The case studies underscored several important aspects of TDSC that are useful for research in the substance abuse field: (1) the TDSC research centers were founded on the explicit mission to facilitate intellectual integration across two or more fields of study; (2) TDSC concepts and practices lend themselves well to an exploration of the complex processes of individual level substance misuse; and (3) TDSC researchers are able to free themselves from the confines of any one discipline to use a transdisciplinary scientific approach. Barriers to a TDSC approach are also outlined and include interpersonal, intrapersonal, environmental, institutional, and organizational circumstances that may hinder a transdisciplinary approach. A conceptual model is provided that outlines the antecedents, processes, and outcomes of TDSC to be used by TSDC practitioners in the study and evaluation of their TDSC process. Tables, figures, glossary, appendixes, bibliography, references