It is likely that mesenchymal stem cells will find use in many autologous regenerative therapies. However, our ability to control stem-cell growth and differentiation is presently limited, and this is a major hurdle to the clinical use of these multipotent cells, especially when considering the desire not to use soluble factors or complex media formulations in culture. Also, the large number of cells required to be clinically useful is currently a hurdle to using materials-based (stiffness, chemistry, nanotopography, etc.) culture substrates. In this chapter we review current aspects of stem-cell response to the nanoenvironment and give a first demonstration of using nanoscale sinusoidal mechanotransductive protocol, “nanokicks”, to promote osteoblastogenesis in human mesenchymal stem-cell cultures. It has been shown that RhoA has a central role in osteoblastic differentiation in agreement with materials-based strategies. It is easy to envisage such stimulation protocols being upscaled to form large-scale bioreactors as standard cell-culture plates and incubators are used in the protocol. Stem-cell reactions to nanoenvironments are different and need more research to be clear but these findings are basic for regenerative therapy and tissue/cell engineering.