Abstract The past 2 decades have witnessed a surge of interest and investment in transdisciplinary research teams and centers. Only recently, however, have efforts been made to evaluate the collaborative processes and scientific and public policy outcomes of these endeavors. This paper offers a conceptual framework for understanding and evaluating transdisciplinary research, and describes a large-scale national initiative, the National Institutes of Health Transdisciplinary Tobacco Use Research Centers (TTURCs) program, undertaken to promote cross-disciplinary scientific collaboration in the field of tobacco use science and prevention. A 5-year evaluation of collaborative processes and outcomes observed across multiple TTURC centers conducted during 1999 to 2004 is described. The findings highlight key contextual circumstances faced by participating centers (i.e., the breadth of disciplines and departments represented by each center, the extent to which members had worked together on prior projects, spatial proximity among researchers’ offices, and frequency of their face-to-face interaction) that influenced their readiness for collaboration and prompted them to follow different pathways toward transdisciplinary integration. Implications of these findings for developing and evaluating future transdisciplinary research initiatives in the field of active living research are discussed.