Introduction: Although chemotherapy is currently indispensable for the treatment of osteosarcoma, chemotherapy for this rare cancer has not been developed based on multicentre randomised prospective trials with many subjects. The therapeutic outcomes of chemotherapy have been improved in large part through the efforts and innovation of physicians who treated patients with osteosarcoma and conducted detailed examinations of a small number of subjects. It is important to understand how chemotherapy for osteosarcoma has changed to achieve further development. Areas covered: This article discusses the changes in chemotherapy for osteosarcoma, including adjuvant and neoadjuvant chemotherapy, and focuses on four key anticancer drugs: methotrexate, adriamycin, cisplatin, and ifosfamide. This article also discusses the problems of research on osteosarcoma treatment, from the perspective of osteosarcoma as a rare disease, and the challenges to be addressed. Expert opinion: Approximately 30 years have passed since the key anticancer drugs were introduced. The development of new therapeutic drugs for osteosarcoma has stagnated. Given that osteosarcoma is a rare cancer, it would be difficult to expect that drug development will be led by pharmaceutical companies. Thus, it is very important to create a system for more efficient drug development based on innovations from various academic and medical institutions.