Purpose of Review Advancements in space travel, such as space tourism into Earth's orbit, but also the prospect of long-distance manned space travel to other celestial bodies such as Mars, has generated a clinical need for new enabling technologies to support the long-term well-being of humans during their passage. Here, we will give an outline on the clinical need and practical considerations to MSC therapy as enabling technology for long-distance manned space travel. Recent Findings Long-distance space travel entails a threat to the health of astronaut crews due to the low gravity environment and exposure to toxic radiation in space. Multi-organ-system degenerative changes, such as decline in musculoskeletal, hematopoietic, immune system function, and in particular risk of genetic mutations and cancer, are major health concerns. Physical training, pharmacological agents, and protective shielding are among the currently available methods to counteract harmful effects. However, a potential lack of adequate shielding, side effects of pharmacological compounds, and limitations to physical training suggest a need for new countermeasures, to protect space travellers to the best extent. Here, the prospect of cell-based therapy, e.g. mesenchymal stromal/stem cells (MSCs), has been subject to intense research, due to their potent regenerative and immunomodulatory properties. Off-the-shelf MSC therapeutics can be easily maintained in space due to the ambient extremely low-temperature environment, and cryorecovery and even culturing of MSCs under microgravity were shown to be feasible. Summary Designing new therapy against harmful radiation is urgent need in space travel. Here we will discuss aspects related to clinical MSC administration to optimize their therapeutic benefit. MSC-based therapy may aid in evolving protective countermeasures for space travellers.