The future of long-duration spaceflight missions will place our vehicles and crew outside of the comfort of low-Earth orbit. Luxuries of quick resupply and frequent crew changes will not be available. Future missions will have to be adapted to low resource environments and be suited to use resources at their destinations to complete the latter parts of the mission. This includes the production of food, oxygen, and return fuel for human flight. In this chapter, we performed a review of the current literature, and offer a vision for the implementation of cyanobacteria-based bio-regenerative life support systems and in situ resource utilization during long duration expeditions, using the Moon and Mars for examples. Much work has been done to understand the nutritional benefits of cyanobacteria and their ability to survive in extreme environments like what is expected on other celestial objects. Fuel production is still in its infancy, but cyanobacterial production of methane is a promising front. In this chapter, we put forth a vision of a three-stage reactor system for regolith processing, nutritional and atmospheric production, and biofuel production as well as diving into what that system will look like during flight and a discussion on containment considerations.