Osteosarcoma is the most prevalent bone tumor in children, adolescents, and young adults. It is considered a systemic disease with micrometastatic spread present already at diagnosis. Hence, while radical surgery is considered a prerequisite to successful treatment of localized or metastatic osteosarcoma, cure can – with few exceptions – only be achieved in combination with intensive chemotherapy. Despite multimodal therapy, 5-year event-free and overall survival for resectable metastatic and localized osteosarcoma have stagnated for almost four decades at <60% and approximately 70%, respectively. Unresectable osteosarcoma has survival rates below 10%. As several clinical trials have failed to improve outcomes with further intensified cytotoxic regimens, other treatment modalities to improve osteosarcoma survival are urgently needed. As osteosarcoma anecdotally and historically was among the first cancers to respond to immunotherapy and at the same time frequently lacks recurrent targetable genetic lesions and only shows moderate responses to tyrosine-kinase inhibitors with broad specificity, immunotherapeutic strategies appear one of the most promising ways to substantially improve long-term survival in both resectable and unresectable osteosarcoma. However, classical immunotherapy with monotherapeutic immune checkpoint inhibitors has had disappointing results. Several case reports and preclinical evidence suggest that immunotherapeutic agents need to be combined with one another and/or chemotherapeutic agents. At the same time, several biomarkers are emerging that might identify subgroups of osteosarcoma that could be particularly susceptible to immunotherapy. This chapter aims to give a biological, preclinical, and clinical overview on the current knowledge of immunotherapy in osteosarcoma as a basis for future efforts to develop effective combinatorial immunotherapies.