Periosteal stem and progenitor cells are pivotal to the growth and lifelong turnover of bone and underpin its capacity to regenerate. Adjusting the potency of this cell population will therefore be critical to the successful generation and application of new bone repair therapies. Following their role in patterning the embryonic skeleton, Hox genes remain regionally expressed in mesenchymal stromal cell populations of the adult skeleton. Here we show that Hoxa10 is most expressed in the most uncommitted periosteal stem cell and that Hox maintains these skeletal stem cells in a multipotential, uncommitted state, thereby preventing their differentiation into bone. We demonstrate that Hoxa10 mediates the reprogramming of periosteal progenitors towards a stem cell state with greater self-renewal capacity and also establish that region-specific Hox genes mediate cell reprogramming in distinct anatomical regions, demonstrating the continued functional relevance of the embryonic Hox profile in adult stem cells. Together, our data describe a master regulator role of Hox in skeletal stem and progenitor cells and help provide insight into the development of cell-based therapies for treatment of at-risk bone fractures and other bone-related ailments.