This article shares lessons learned in applying system evaluation theory (SET) to evaluate a Clinical and Translational Research Center (CTR) funded by the National Institutes of Health. After describing how CTR support cores are intended to work interdependently as a system, the case is made for SET as the best fit for evaluating this evaluand. The article then details how the evaluation was also challenged to facilitate a CTR culture shift, helping support cores to move from working autonomously to working together and understanding how the cores' individual operating processes impact each other. This was achieved by incorporating the Homeland Security Exercise and Evaluation Program (HSEEP) building block approach to implement SET. Each of the seven HSEEP building blocks is examined for alignment with each of SET's three steps and the ability to systematically support the goal of moving CTR cores toward working interdependently. The implications of using HSEEP to support SET implementation for future evaluations are discussed.