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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. Establishing sustainable approaches for human space exploration is key to achieve independency from terrestrial resources, as well as for ethical considerations. Here the authors highlight microbial biotechnologies that will support sustainable processes for space-based in situ resource utilization and loop-closure, and may be translatable to Earth applications.