Cancer is being reinterpreted due to recent discoveries related to epigenetic regulation during development, and the importance of epigenetic mechanisms in initiation and progression of cancer has been further highlighted by the recent explosion in medical information. Osteosarcoma is highly genetically unstable, and current therapeutic regimens are subject to chemoresistance and tumor relapse. Understanding the epigenetic mechanisms in the pathogenesis of osteosarcoma will provide novel avenues for cancer therapy. In this review, we examine the epigenetic alterations in gene expression in osteosarcoma, and discuss the utilization of epigenetic regulation therapy in treatment against osteosarcoma.