The past two decades have seen a growing interest and investment in transdisciplinary research teams and centers. The Transdisciplinary Tobacco Use Research Centers (TTURCs) exemplify large-scale scientific collaborations undertaken for the explicit purpose of promoting novel conceptual and methodological integrations bridging two or more fields. Until recently, few efforts have been made to evaluate the collaborative processes, and the scientific and public policy outcomes, of such centers. This manuscript offers a conceptual framework for understanding and evaluating transdisciplinary science and describes two ongoing evaluation studies covering the initial phase of the TTURC initiative. The methods and measures used by these studies are described, and early evaluative findings from the first 4 years of the initiative are presented. These data reveal progress toward intellectual integration within and between several of the TTURCs, and cumulative changes in the collaborative behaviors and values of participants over the course of the initiative. The data also suggest that different centers may follow alternative pathways toward transdisciplinary integration and highlight certain environmental, organizational, and institutional factors that influence each center's readiness for collaboration. Methodological challenges posed by the complexities of evaluating large-scale scientific collaborations (including those that specifically aspire toward transdisciplinary integrations spanning multiple fields) are discussed. Finally, new directions for future evaluative studies of transdisciplinary scientific collaboration, both within and beyond the field of tobacco science, are described.