ABSTRACT Multipotent mesenchymal stem/stromal cells (MSCs) are used in a large number of regenerative/reparative clinical applications and tissue engineering approaches. Translational outcomes from the use of these cells in various contexts vary widely and generating new musculoskeletal tissue that is both functional and able to integrate appropriately in vivo remains a major challenge. Recent research from several laboratories have refined and advanced the field's ability to enrich for MSCs/stromal cells with high progenitor potential, but a recent study from my laboratory reveals that MSCs from the bone marrow of different bones of the adult skeleton maintain the regionally restricted, unique Hox expression profile that is established during development (Rux, et al., Dev. Cell, 2016). Hox expression is only observed in progenitor-enriched MSC populations (PDGFR?+/CD51+, LepR-Cre labeled) and is not detected in differentiated skeletal cell types or in non-progenitor enriched (LepR-negative) non- endothelial stroma. Further, fracture repair studies demonstrate that Hox11 genes function in the central limb regions (zeugopod: radius/ulna, tibia/fibula) in adult MSC populations and loss of Hox11 function leads to the inability of MSC progenitors to differentiate towards cartilage and bone (but has no effect on adipose differentiation). This leads to the broader question of whether unique Hox expression patterns in MSCs are a by-product of development and function via a common mechanism after developmental patterning stages to promote general MSC potential. Alternatively, the much more interesting and biologically significant possibility is that unique Hox genes or paralogs may function differentially in spatially distinct MSCs to provide region-specific regulatory information during growth, maintenance and repair through adult stages. This has critical implications for the use of MSCs in musculoskeletal tissue engineering and regenerative approaches as the unique functional and regulatory characteristics of MSCs may differ considerably depending on their origin; this could profoundly impact their performance in clinical and tissue engineering applications.