Progress in multimodal therapy has contributed to a marked improvement in the clinical outcome of Ewing’s sarcoma family of tumors (ESFT) and osteosarcoma, which are the most common malignant bone tumors in children, adolescents, and young adults. However, the prognosis of patients whose bone tumors recurred during therapy or relapsed after treatment remains poor. The objective response rate of recently developed salvage chemotherapies for recurrent or refractory ESFT is approximately 50%, whereas that of molecular target therapy ranges from 10 to 20%, with a transient therapeutic effect. Local treatment (surgery and radiotherapy) for primary site or metastatic lesions may contribute to the increase in the survival rate. By contrast, the efficacy of hematopoietic cell transplantation (HCT) remains controversial. Because the objective response rate of salvage chemotherapy or molecular target therapy for recurrent or refractory osteosarcoma is low, aggressive local treatment of recurrent or refractory lesions is essential to obtain long-term survival. There is no consensus on the efficacy of HCT. There are very few patients with both diseases who achieved long-term survival by molecular target drug monotherapy because of the evolution of drug resistance. Furthermore, the prognosis of patients who experience relapse or progression during therapy was quite dismal. Further studies will be required to verify the optimal use of molecular target drugs and to develop cellular immunotherapy, such as chimeric antigen receptor T-cell therapy, for the improvement of the clinical outcome of recurrent or refractory malignant bone tumors.