Stem cells are the cell of origin for organisms and their organs. These cells are critical for tissue regeneration, as well as regenerative medicine. Mechanical forces, such as gravity, have been demonstrated to provide important signals for stem cell fate. In fact, the absence of gravity, that is, microgravity, affects almost all aspects of human physiology, which has been partly attributed to changes in the biological behaviors of stem cells. In this review, we summarize the current understanding of the effects of microgravity on stem cell differentiation that control the fate of stem cells.