For patients with osteosarcoma, the development of metastases, often to the lungs, is the most common cause of death. Long-term outcomes for patients who present with localized or disseminated disease have largely remained unchanged over the past 20 years. Further improvements in outcome are not likely to come from intensification of cytotoxic chemotherapy; as such, new targets for treatment are needed. A view toward such targets in osteosarcoma may be constructed based on three common clinical features of the disease. These include the origin of osteosarcoma in the bone or primitive mesenchymal cells, the predictable process of metastatic progression characterized by this disease, and the development of metastatic lesions almost exclusively in the lung. It is likely and potentially favorable for some targets to be relevant for more than one process. This review summarizes novel targets under evaluation for the treatment of osteosarcoma based on these three features of the disease.