Bone marrow-derived multipotent stem and stromal cells (MSCs) are likely candidates for cell-based therapies for various conditions including skeletal disease. Advancement of these therapies will rely on an ability to identify, isolate, manipulate, and deliver stem cells in a safe and effective manner. Although it is clear that physical signals affect tissue morphogenesis, stem cell differentiation, and healing processes, integration of mechanically induced signaling events remain obscure. Mechanisms underlying sensation and interpretation of mechanical signals by stem cells are the focus of intense study. External mechanical signals have the ability to activate osteogenic signaling pathways in MSCs including Wnt, Ror2, and Runx2. It is also clear that intracellular tensile forces resulting from cell-extracellular matrix interactions play a critical role in MSC regulation. Further work is required to determine the precise role that mechanical forces play in stem cell function.