The skeleton is a self-renewing tissue, but what is the source of the stem cells that drive this renewal? Given the skeleton's dual embryonic origin -the cranium is derived from the neural crest (NC), the rest of the skeleton arises from mesoderm - are there one or two populations of skeletal stem cells? Now, on p. 2845, Jill Helms and colleagues report that two such populations exist in mice, and that their embryonic origin and Hox status influence their fate during adult bone regeneration. Using genetic cell labelling, they show that NC-derived skeletal stem cells heal injured mandibles and that mesoderm-derived stem cells heal tibial defects. In grafting experiments,although NC-derived stem cells heal both mandibular and tibial injuries,mesoderm-derived stem cells heal only tibial injuries, a limitation that is attributable to a mismatch between Hox expression in the host and donor cells. The researchers propose that this molecular difference gives skeletal stem cells a `positional memory' that may influence the outcome of bone grafts.