Abstract: Mesenchymal stem cells hold great promise for musculoskeletal regenerative medicine, given their ability to both produce functional tissues ex vivo as well as participate in endogenous repair. These cells are responsive to both soluble factors and biophysical cues that reside within their microenvironment. Ultimately, these cells sum this information to make decisions regarding lineage commitment and function. This seminar will detail how both ‘passive’ and ‘active’ cues regulate MSC fate decisions, with a particular emphasis on the role of mechanical inputs in the regulation of cell behavior. Examples will include material modifications that alter cell signaling to control how cells sense the mechanics of the microenvironment, as well as how dynamic mechanical inputs are transmitted through the cell and to the nucleus to alter cell structure, function, and fate decisions.