Synthetic hydrogels have ideal physiochemical properties to serve as reductionist mimics of the extracellular matrix (ECM) for studies on cellular mechanosensing. These studies range from basic observation of correlations between ECM mechanics and cell fate changes to molecular dissection of the underlying mechanisms. Despite intensive work on hydrogels to study mechanobiology, many fundamental questions regarding mechanosensing remain unanswered. In this review, I first discuss historical motivation for studying cellular mechanobiology, and challenges impeding this effort. I next overview recent efforts to engineer hydrogel properties to study cellular mechanosensing. Finally, I focus on in vitro modeling and cell-based therapies as applications of hydrogels that will exploit our ability to create micro-environments with physiologically relevant elasticity and viscoelasticity to control cell biology. These translational applications will not only use our current understanding of mechanobiology but will also bring new tools to study the fundamental problem of how cells sense their mechanical environment. STATEMENT OF SIGNIFICANCE: Hydrogels are an important tool for understanding how our cells can sense their mechanical environment, and to exploit that understanding in regenerative medicine. In the current review, I discuss historical work linking mechanics to cell behavior in vitro, and highlight the role hydrogels played in allowing us to understand how cells monitor mechanical cues. I then highlight potential translational applications of hydrogels with mechanical properties similar to those of the tissues where cells normally reside in our bodies, and discuss how these types of studies can provide clues to help us enhance our understanding of mechanosensing.