Astronauts experience weightlessness-induced bone loss due to an unbalanced process of bone remodeling that involves bone mesenchymal stem cells (bMSCs), as well as osteoblasts, osteocytes, and osteoclasts. The effects of microgravity on osteo-cells have been extensively studied, but it is only recently that consideration has been given to the role of bone MSCs. These live in adult bone marrow niches, are characterized by their self-renewal and multipotent differentiation capacities, and the published data indicate that they may lead to interesting returns in the biomedical/bioengineering fields. This review describes the published findings concerning bMSCs exposed to simulated/real microgravity, mainly concentrating on how mechanosignaling, mechanotransduction and oxygen influence their proliferation, senescence and differentiation. A comprehensive understanding of bMSC behavior in microgravity and their role in preventing bone loss will be essential for entering the future age of long-lasting, manned space exploration.