The therapeutic efficacy of human mesenchymal stem cells (hMSCs) depends on proper characterization and control of their unique biological, mechanical and physicochemical properties. For example, cellular biomechanics and environmental mechanical cues have been shown to critically influence cell commitment to a particular lineage. We characterized biomechanical properties of hMSCs including cytoskeleton elasticity and plasma membrane/cytoskeleton coupling. As expected, during osteogenic differentiation of hMSCs, the cellular biomechanics is remodeled, and such remodeling precedes up-regulation of the osteogenic markers. Further, application of an electrical stimulation modulates the cellular biomechanics and therefore may be used to facilitate stem cell differentiation for stem cell-based tissue engineering.