Since the introduction of multi-agent chemotherapy for osteosarcoma over 30 years ago, overall survival has exceeded 50%. A clear understanding of the acute complications and late effects of osteosarcoma therapy is required to care effectively for patients with osteosarcoma undergoing active treatment, and for the increasing number of osteosarcoma survivors. There has now been sufficient cumulative experience treating patients with osteosarcoma with active anti-osteosarcoma chemotherapy agents, high-dose methotrexate, doxorubicin, cisplatin, ifosfamide, and etoposide to recognise and understand rare toxicities associated with these agents, and to identify the late effects of osteosarcoma therapy. Late effects and rare toxicities of osteosarcoma include cardiac toxicity, acute and chronic nephrotoxicity, neurotoxicity, hearing loss, infertility, and second malignant neoplasms. Reducing the complications of osteosarcoma therapy is an important goal that will require the identification of clear prognostic indicators, the development of biologically-based therapies, and improved antidotes for the active anti-osteosarcoma cytotoxic drugs.