Osteosarcoma is a disease with many complex genetic abnormalities but few well defined genetic drivers of tumor initiation and evolution. The disease is diagnosed and defined through the observation of malignant osteoblastic cells that produce osteoid, however the exact cell of origin for this cancer remains to be definitively defined. Evidence exists to support a mesenchymal stem cell as well as committed osteoblast precursors as the cell of origin. Increasing numbers of experimental models have begun to shed light on to the likely cell population that gives rise to OS in vivo with the weight of evidence favoring an osteoblastic population as the cell of origin. As more information is gathered regarding osteosarcoma initiating cells and how they may relate to the cell of origin we will derive a better understanding of the development of this disease which may ultimately lead to clinical improvements through more personalized therapeutic approaches.