Osteosarcoma is the most common primary bone tumor in childhood and adolescence. The use of combination chemotherapy and surgery enables long-term survival in approximately 60-70% of cases. However, the necessity for surgery, the poor prognosis of patients with metastatic or recurrent disease (long-term survival in only about 20% of cases), and the lack of establishment of second-line chemotherapy suggest that improvements in chemotherapy are desperately needed. Currently, in an effort to extend the protocol with the chemotherapy drugs that already exist, high-dose chemotherapy with/without autologous peripheral blood stem cell transplantation, and tumor-targeted drug delivery systems are under investigation. Future drug developments will no doubt lie in the direction of immunotherapy and anti-angiogenic therapy, as well as the use of cytotoxic drugs. Identifying the genes and signal transduction pathways responsible for the development of osteosarcoma or for the occurrence of malignancy in cases of osteosarcoma will undoubtedly lead to the identification of pathway-specific agents, or possible gene therapy. Furthermore, as increased light is shed on the character of osetoblastic differentiation in osteosarcoma, this will certainly give rise to new treatments utilizing differentiation therapy. This article reviews the current status and perspectives regarding the treatment of osteosarcoma in terms of chemotherapy.