The ability of human cells to adapt to space radiation is essential for the well-being of astronauts during long-distance space expeditions, such as voyages to Mars or other deep space destinations. However, the adaptation of the microbiomes should not be overlooked. Microorganisms inside an astronaut’s body, or inside the space station or other spacecraft, will also be exposed to radiation, which may induce resistance to antibiotics, UV, heat, desiccation, and other life-threatening factors. Therefore, it is essential to consider the potential effects of radiation not only on humans but also on their microbiomes to develop effective risk reduction strategies for space missions. Studying the human microbiome in space missions can have several potential benefits, including but not limited to a better understanding of the major effects space travel has on human health, developing new technologies for monitoring health and developing new radiation therapies and treatments. While radioadaptive response in astronauts’ cells can lead to resistance against high levels of space radiation, radioadaptive response in their microbiome can lead to resistance against UV, heat, desiccation, antibiotics, and radiation. As astronauts and their microbiomes compete to adapt to the space environment. The microorganisms may emerge as the winners, leading to life-threatening situations due to lethal infections. Therefore, understanding the magnitude of the adaptation of microorganisms before launching a space mission is crucial to be able to develop effective strategies to mitigate the risks associated with radiation exposure. Ensuring the safety and well-being of astronauts during long-duration space missions and minimizing the risks linked with radiation exposure can be achieved by adopting this approach.