Human pluripotent stem cells (hPSCs) are self-renewing and have the potential to differentiate into any cell type in the body, making them attractive cell sources for applications in tissue engineering and regenerative medicine. However, in order for hPSCs to find use in the clinic, the mechanisms underlying their self-renewal and lineage commitment must be better understood. Many technologies that have been developed for the maintenance and directed differentiation of hPSCs involve the use of soluble growth factors, but recent studies suggest that other elements of the hPSC microenvironment also influence the growth and differentiation of hPSCs. This includes the influences of cell-cell interactions, substrate mechanics, cellular interactions with extracellular matrix, as well as the nanotopography of the substrate and physical forces such as shear stress, cyclic mechanical strain, and compression. In this review, we highlight the recent progress of this area of research and discuss ways in which the mechanical cues may be incorporated into hPSC culture regimes to improve methods for expanding and differentiating hPSCs.