Stem cell engineering is a distinct field at the intersection of stem cell biology, engineering and regenerative medicine. The understanding of how biophysical and biochemical cues in the cells’ surrounding regulate cell fate and differentiation can be harnessed for the development of novel approaches to modulate stem cell behaviors and leading eventually to their clinical utilization. As stem cell knowledge matures, its appropriate translation to the clinical setting is crucial for success. Thus, in addition to fundamental studies, approaches to monitor stem cell responses, enhance regeneration through material properties, uncover the immunological response during regeneration and the accurate design of clinical trials are all required to unlock the therapeutic potential of stem cells.