NASA has an elaborate process for identifying and mitigating technical risks in its human space exploration program. However, non-technical risks—political, economic, and societal—are not captured in this process. Such risks are large in number, diverse in character, often unpredictable, and can be impossible to prevent because they are beyond the space agency's control. NASA's mission directorates are responsible for long-term strategic planning, so despite the difficulties, the Exploration Systems Mission Directorate (ESMD) must direct its attention to long-term sustainability risks and the development of mitigation plans. This article surveys long-term risk factors and, where possible, makes suggestions on mitigation approaches for consideration by ESMD and NASA's top management.