This edited volume makes the case that a systems approach is needed for long-term spaceflight missions. Due to distance from Earth and the impossibility of resupply or rapid return, these flights will entail unprecedented autonomy on the part of the crew. This autonomy includes the need for local clinical decision support and other assistance with urgent medical concerns. The advantage of a systems approach to medical needs in human spaceflight is that it enables a systematic and repeatable methodology for identifying and developing the individual pieces of the spacecraft systems based on the human system needs that are unique to that problem and environment.The book begins by introducing a systems basis for thinking about humans in space. It describes existing models and paradigms of systems medicine, as well as the tools and analytical approaches involved. A tantalizing peek at preliminary applications of systems medicine in NASA is provided. As systems in human spaceflight continue to evolve for the foreseeable future, it is argued that a systems approach will help to ensure that the evolution of the relevant sub-systems is centered on optimal human-system function across the unique spaceflight needs of the developing customer base. The discussions on balancing the needs of the mission versus the maintenance of crew health, medical risk and liability for commercial spaceflights, and the need to anticipate what the next medical issues might be, will hopefully leave readers cautiously optimistic about this new frontier of applied science.