Osteosarcoma (OS) development and nuclear receptor agonist-mediated differentiation therapy. OS can be regarded as a differentiation disease, which is caused by disruptions of the terminal osteogenic differentiation. The stage and nature of differentiation defects may determine the aggressiveness of OS tumors. PPAR$\gamma$ agonists and/or retinoids have been shown to inhibit OS proliferation, induce apoptosis, and promote osteogenic differentiation. Thus, these agents can be used as differentiation therapy, in combination with conventional chemotherapy, for OS treatment.