Multiple molecular and physical cues engage in complex interplay to afford the fine control over stem cell behavior that is required during tissue development, homeostasis, and repair. As a result of a close collaboration between biologists, engineers, and physicists over the past decade, the types of mechanical parameters which influence stem cells, along with the corresponding cellular outcomes, have started to emerge. Moreover, the field has begun to identify the molecular structures and mechanisms whereby stem cells sense physical signals and transduce them into biological response. In this chapter, we survey the existing knowledge of stem cell mechanobiology and discuss bioengineering approaches which hold the potential to address outstanding questions and concepts. In particular, we cover approaches which may help dissect the context-dependent influence ofthe physical environment, and resolve its interactions with molecular signals. We also describe platforms which could recreate the spatial and temporal variations in mechanics which are present in vivo and may play a role in patterning stem cell behaviors. Comprehensive understanding of the complex mechanical regulation of stem cell fate may bring us closer to taking full advantage of their vast regenerative potential.