A stem cell in its microenvironment is subjected to a myriad of soluble chemical cues and
mechanical forces that act in concert to orchestrate cell fate. Intuitively, many of these soluble
and biophysical factors have been the focus of intense study to successfully influence and direct
cell differentiation in vitro. Human pluripotent stem cells (hPSCs) have been of considerable
interest in these studies due to their great promise for regenerative medicine. Culturing and
directing differentiation of hPSCs, however, is currently extremely labor-intensive and lacks the
efficiency required to generate large populations of clinical-grade cells. Improved efficiency may
come from efforts to understand how the cell biophysical signals can complement biochemical
signals to regulate cell pluripotency and direct differentiation. In this concise review, we explore
hPSC mechanobiology and how the hPSC biophysical microenvironment can be manipulated to
maintain and differentiate hPSCs into functional cell types for regenerative medicine and tissue
engineering applications.