The most prevalent primary malignant bone tumor affecting children and adolescents is osteosarcoma. Osteosarcoma is characterized by the formation of immature bone or osteoid tissue by neoplastic cells. They arise predominantly in the long bones, occasionally in the axial bones, and seldom in the soft tissues. Patients with osteosarcoma are currently treated with preoperative (neoadjuvant) chemotherapy followed by tumor resection and further postoperative chemotherapy. Wide margin resection often is necessary and leaves large bone defects. These defects must be reconstructed and repaired using appropriate materials and methods to restore function and structure. Currently, autograft, allograft, prosthetic implant, or a combination is used for defect reconstruction. Despite the available options, reconstruction of large bone defects and improvement in survival rates are still challenging. Tissue engineering and regenerative medicine (TERM) may be promising alternative strategies to regenerate bone and may change conventional treatment strategies in patients with osteosarcoma. TERM in the form of scaffolds, healing promotive factors, or stem cells could be designed to be useful for bone reconstruction and regeneration and also for delivery of anti-cancer therapeutic agents. Combining TERM approaches with immunotherapy, chemoimmunotherapy, radioimmunotherapy, and gene therapy together with advances in diagnostic procedures may change palliative results to curative achievements in the future. This review comprehensively discusses current options, challenges, possible strategies, and future directions in managing patients with osteosarcoma.