It is crucial to elucidate the mechano-biological coupling mechanisms of how (micro-)gravity affects the vital processes and biological responses at cellular and molecular levels.Scientific issues are mainly focused on the following aspects: 1) How do the terrestrial organisms sense (micro-)gravity signals and what are the underlying mechanotransduction pathways? 2) How do the organisms adapt themselves to the (micro-)gravity environment? 3) How can we utilize the (micro-)gravity resource to promote space life science and develop space biotechnology? Here we propose, from the viewpoint of mechano-biological coupling in space, to elucidate the mechanical stimuli oncellular responses using a combined approach that coordinates biological function, mechanical measurements, and numerical calculations, and to develop the novel assays and techniques for both ground-based and space-payload tests.Typical case studies included are to reveal the mechanical stability of cells under gravity-directed vector and to uncover the impact of flow-induced mass transportation on cell growth in a space or ground-based bioreactor.These studies provide the bases in understanding mechanobiology of cellular responses to (micro-)gravity and establish an integrated platform for ground-based studies.Finally, the progresses of ongoing space mission validation are discussed.