Sensitivity of the human immune system to microgravity has been supposed since the first Apollo missions and was demonstrated during several space missions in the past. In vitro experiments demonstrated that cells of the immune system are exceptionally sensitive to microgravity. Therefore, serious concerns arose whether spaceflight-associated immune system weakening ultimately precludes the expansion of human presence beyond Earth’s orbit. In human cells, gravitational forces may be sensed by an individual cell in the context of altered extracellular matrix mechanics, cell shape, cytoskeletal organization, or internal prestress in the cell–tissue matrix. The development of cellular mechanosensitivity and signal transduction was probably an evolutionary requirement to enable our cells to sense their individual microenvironment. Therefore it is possible that the same mechanisms, which enable human cells to sense and to cope with mechanical stress, are potentially dangerous in microgravity. This chapter reviews the most recent developments in investigation to elucidate the influence of microgravity on immune cell signaling and functions and hereby bridges the phenotypic changes to transcriptome and epigenetic regulators.