Hox genes are evolutionarily conserved transcription factors that during embryonic development function as master regulators of positional identity. In postnatal life, the function of Hox proteins is less clear: Hox genes are expressed during tissue repair, but in this context their function(s) are largely unknown. Here we show that Hox genes are expressed in periosteal stem/progenitor cells in a distribution similar to that during embryonic development. Using unbiased sequencing, we established that periosteal stem/progenitor cells from distinct anatomic sites within the skeleton significantly differ in their transcriptome, and that Hox expression status best defines these differences. Lastly, we provide evidence that Hox gene expression is one potential mechanism that maintains periosteal stem/progenitor cells in a more primitive, tripotent state, while suppression of Hox genes leads to fate changes with loss of tripotency. Together, our data describe an adult role of Hox genes other than positional identity, and the modulatory role of Hox genes in fate decisions may offer potential druggable targets for the treatment of fractures, non-unions and bone defects.