A human spaceflight to Mars is scheduled for the next decade. In preparation for this unmatched endeavor, a plethora of challenges must be faced prior to the actual journey to Mars. Mission success will depend on the health of its crew and its working capacity. Hence, the journey to Mars will also depend on the microbiome and its far-reaching effects on individual crew health, the spaceship’s integrity, and food supply. As human beings rely on their microbiome, these microbes are essential and should be managed to ensure their beneficial effects outweigh potential risks. In this commentary, we focus on the current state of knowledge regarding a healthy (gut) microbiome of space travelers based on research from the International Space Station and simulation experiments on Earth. We further indicate essential knowledge gaps of microbial conditions during long-term space missions in isolated confined space habitats or outposts and give detailed recommendations for microbial monitoring during pre-flight, in-flight, and post-flight. Finally, the conclusion outlines open questions and aspects of space traveler’s health beyond the scope of this commentary.