As renewed interest in human space-exploration intensifies, a coherent and modernized strategy for mission design and planning has become increasingly crucial. Biotechnology has emerged as a promising approach to increase resilience, flexibility, and efficiency of missions, by virtue of its ability to effectively utilize in situ resources and reclaim resources from waste streams. Here we outline four primary mission-classes on Moon and Mars that drive a staged and accretive biomanufacturing strategy. Each class requires a unique approach to integrate biomanufacturing into the existing mission-architecture and so faces unique challenges in technology development. These challenges stem directly from the resources available in a given mission-class-the degree to which feedstocks are derived from cargo and in situ resources-and the degree to which loop-closure is necessary. As mission duration and distance from Earth increase, the benefits of specialized, sustainable biomanufacturing processes also increase. Consequentially, we define specific design-scenarios and quantify the usefulness of in-space biomanufacturing, to guide techno-economics of space-missions. Especially materials emerged as a potentially pivotal target for biomanufacturing with large impact on up-mass cost. Subsequently, we outline the processes needed for development, testing, and deployment of requisite technologies. As space-related technology development often does, these advancements are likely to have profound implications for the creation of a resilient circular bioeconomy on Earth.

Finding sustainable approaches to achieve independence from terrestrial resources is of pivotal importance for the future of space exploration. This is relevant not only to establish viable space exploration beyond low Earth–orbit, but also for ethical considerations associated with the generation of space waste and the preservation of extra-terrestrial environments. Here we propose and highlight a series of microbial biotechnologies uniquely suited to establish sustainable processes for in situ resource utilization and loop-closure. Microbial biotechnologies research and development for space sustainability will be translatable to Earth applications, tackling terrestrial environmental issues, thereby supporting the United Nations Sustainable Development Goals.