Many nations are expanding or initiating nuclear energy programs as part of a national energy portfolio. Transitioning to advanced nuclear energy systems improves sustainability and promotes energy independence. These advanced nuclear energy systems also must be shown to enhance safety, safeguards, and security in order to be realistically deployed. This is of particular concern to non–nuclear weapons states, to assure compliance with International Atomic Energy Agency treaty obligations. Consequently, the relatively new research area of safeguardability addresses how to integrate goals for safety, safeguards, and security as part of a design strategy for an advanced fuel cycle. This paper presents an overall set of principles that form the foundation of a comprehensive safeguardability methodology, including the quantitative modeling studies derived therein. Results show an approach for characterizing used fuel, functional components to engineering design for nuclear materials handling facilities, and repository analysis. We conclude with an argument for the necessity of an integrative, systems assessment approach to the safeguardability of an advanced fuel cycle.