The purpose of this handbook is to facilitate a repeatable and robust process that promotes clear and effective interfaces between activities and stakeholders focused on meeting nuclear flight safety requirements for missions utilizing space nuclear systems (SNS), within the context of NASA’s broader nuclear-related activities and interfaces. NPR 8715.26, Nuclear Flight Safety, requires that the NASA project manager “incorporate nuclear flight safety considerations starting with program or project formulation through the point at which the SNS or other radioactive material no longer has the potential to affect Earth’s biosphere.” NASA’s use of SNS inherently involves partnering with other stakeholders to conduct a range of related activities that interface with nuclear flight safety. From a categorical perspective these include: (i) meeting the authorities and licensing requirements for possession and use of nuclear material, as governed by other Federal authorities; (ii) conducting National Environmental Policy Act (NEPA) activities for nuclear-enabled missions; (iii) meeting Federal nuclear launch authorization requirements; (iv) conducting radiological contingency planning activities, including those associated with international commitments; (v) performing risk communication and public outreach activities; and (vi) ensuring decommissioning and disposal strategies reflect National policies and interests. It is the intent of this handbook to promote an effective interface between nuclear flight safety and these interrelated categorical activities. In addition to activities undertaken with partnering agencies, there are individual nuclear-related activities and programs that have a nexus to nuclear flight safety, and these include: (i) applicable NASA Standing Review Boards; (ii) the US Department of Energy nuclear safety activities conducted in partnership with NASA under Memoranda of Understanding; (iii) the Department of Defense’s Range Safety activities; (iv) NASA’s general involvement in interagency and international dialogues regarding nuclear safety; (v) the NASA-administered Interagency Nuclear Safety Review Board; (vi) NASA’s program and project governance activities and nuclear-specific Technical Discipline Team activities under the Office of the Chief Engineer; and others. It is the intent of this handbook to promote effective leveraging of these additional interrelated organizational activities, as appropriate.