For malignant tumors, early micro-metastases are an important feature. In addition to local treatment such as surgery and radiotherapy, chemotherapy is often needed in conjunction with it. in 1942, Lindskog first applied an alkylating agent for chemical warfare, nitrogen mustard, to the treatment of Hodgkin’s disease and achieved transient remission. This is considered to be the beginning of modern chemotherapy for malignant tumors. The application of chemotherapy to the treatment of malignant bone tumors has been developed in the last three decades, and during this period, there has been a rapid development in the development of chemotherapeutic drugs, the methods of chemotherapy, and the effects of chemotherapy. In particular, the development of the concept of Neo-adjuvant chemotherapy and the application of its rules have led to great progress in the treatment of malignant bone tumors. Chemotherapy has become as important as surgical treatment, radiotherapy, immunotherapy, etc. In the case of osteosarcoma, for example, its main treatment before the introduction of chemotherapy was amputation or extensive local excision followed by adequate radiation therapy, which often resulted in lifelong disability of the patient, with a survival rate of less than 20% and a high rate of local recurrence, until adjuvant chemotherapy was added to the overall treatment regimen, especially by Norman Jaffe in 1972, using high-dose methotrexate plus tetrahydrofolate relief (HD- MTX-CF) for the treatment of osteosarcoma. This chemotherapeutic approach is considered a turning point in the treatment of osteosarcoma. The use of chemotherapeutic agents has led to substantial improvements in prognosis, with 5-year survival rates ranging from 20% before the 1970s to 70% to 80% today. The possibility and success rate of limb-preserving reconstructive surgery is greatly improved by neoadjuvant chemotherapy. The principles and methods of chemotherapy for bone tumors are derived from extensive clinical practice, and they have gone through the following stages: initial single-drug adjuvant chemotherapy; combination chemotherapy with multiple drugs and maximum tolerated dose (dose-intensity) chemotherapy; chemotherapy when metastatic lesions appear clinically (adjuvant chemotherapy); and chemotherapy preceding other treatments (neoadjuvant chemotherapy). The regimen and efficacy of combination chemotherapy for malignant bone tumors depends on the histology and extent of the lesion. Principles for the selection of combination chemotherapy drugs include: application of drugs proven to be active against the tumor alone, which should obtain additive or synergistic effects without increasing cytotoxicity and overcoming the development of drug resistance. Adjuvant chemotherapy generally refers to the application of antineoplastic drugs after surgical control of local tumors to treat microscopic lesions that may metastasize to the lungs, bones, lymph nodes, and other sites. Osteosarcoma and Ewing sarcoma have been shown in extensive clinical practice to be very effective with adjuvant chemotherapy, with significant improvements in five-year survival rates. Another major chemotherapy advancement in the 1970s was the advent of preoperative chemotherapy, and this modality subsequently became known as neoadjuvant chemotherapy. Since then chemotherapy has no longer been used solely to improve patient survival and reduce local recurrence and metastasis rates, but also to improve limb preservation rates. Neoadjuvant chemotherapy has been used for many years and has become the standard of care for osteosarcoma since the early 1990s. Although its impact on whether it can increase the five-year survival rate compared with postoperative adjuvant chemotherapy remains to be further observed, neoadjuvant chemotherapy can provide early treatment of microscopic metastases, kill the primary tumor as well, and facilitate subsequent limb preservation therapy, as well as provide information for in vivo chemotherapy sensitivity testing by assessing the tumor response to chemotherapy.