We investigate the implementation of the principles of systems engineering in the U.S. Department of Energy’s Fuel Cycle Technologies (FCT) Program to provide a framework for achieving its long-term mission of demonstrating and deploying sustainable nuclear fuel cycle options. A fuel cycle “screening” methodology is introduced that provides a systematic, objective, and traceable method for evaluating and categorizing nuclear fuel cycles according to their performance in meeting sustainability objectives. The goal of the systems engineering approach is to transparently define and justify the research and development (R&D) necessary to deploy sustainable fuel cycle technologies for a given set of national policy objectives. The approach provides a path for more efficient use of limited R&D resources and facilitates dialog among a variety of stakeholder groups interested in U.S. energy policy. Furthermore, the use of systems engineering principles will allow the FCT Program to more rapidly adapt to future policy changes, including any decisions based on recommendations of the Blue Ribbon Commission on America’s Nuclear Future. Specifically, if the relative importance of policy objectives changes, the FCT Program will have a structured process to rapidly determine how this impacts potential fuel cycle performance and the prioritization of needed R&D for associated technologies.