With the introduction of effective systemic chemotherapy, the prognosis for patients with osteosarcoma has improved dramatically. Estimates of overall survival for osteosarcoma patients prior to 1975 ranged from 5 to 20%, even for patients with localized disease of the extremity treated with amputation. The majority of these patients eventually developed pulmonary metastases and succumbed to their disease. The introduction of effective chemotherapy has dramatically improved the outcome of patients with localized disease, but has not altered the survival of patients with metastatic disease. Moreover, there has been little, if any, improvement in the outcomes of patients with localized disease since the mid-1980s. This has led to the investigation of other treatment approaches, including immunotherapy. Coincident with the initial development of chemotherapy, there were early attempts at immunotherapy. These met with little success. Subsequent approaches to harnessing the immune system have yielded more encouraging results. This chapter will review these various approaches, highlighting the role that immunotherapy might play in the multi-modality treatment of localized and metastatic osteosarcoma.