Pediatric osteosarcoma is most commonly diagnosed during adolescence and young adulthood and requires treatment with surgical intervention and intensive chemotherapy. While the exact molecular mechanism leading to osteosarcoma has yet to be elucidated, some syndromes and genetic conditions have been associated with development of the disease. Treatment of osteosarcoma has always included surgical intervention with amputation being most common prior to the introduction of multi-agent chemotherapy. The introduction of multi-agent chemotherapy along with improved surgical techniques have allowed increasing use of limb-salvage surgery. Current investigations including the use of modern chemotherapy show no detectable survival difference between amputation and limb salvage surgery. Standard neo-adjuvant and adjuvant regimens using a combination of doxorubicin, cisplatin and methotrexate, with or without ifosfamide have become the standard in the medical management of osteosarcoma. Other newer agents, such as HER2 receptor monoclonal antibody and muramyl tripeptide phosphatidylethanolamine have also been investigated and are included in this review.