Real-time system-wide safety assurance (RSSA) is one of six focus areas for the National Aeronautics and Space Administration (NASA) aeronautics program. NASA envisions that an RSSA system would provide a continuum of information, analysis, and assessment that supports awareness and action to mitigate risks to safety. Maintaining the safety of the NAS as it evolves will require a wide range of safety systems and practices, some of which are already in place and many of which need to be developed. This report identifies challenges to establishing an RSSA system and the high-priority research that should be implemented by NASA and other interested parties in government, industry, and academia to expedite development of such a system.