Osteosarcoma is the most common primary malignant bone tumor which occurs mainly in children and adolescents. Due to rarity, heterogeneity, metastatic potency, and poor response rates to conventional systemic therapy, individualized precision oncology and novel drug discovery in osteosarcoma are warranted. Toward this goal, our laboratory has established the patient-derived orthotopic xenograft (PDOX) model using surgical orthotopic implantation (SOI). In the case of osteosarcoma PDOX, the primary tumors are implanted in the femur and metastatic tumors are implanted in the corresponding place of nude mice. Many promising results have been obtained using the sarcoma PDOX model for identifying effective approved drugs and experimental therapeutics, as well as combinations of them for individual patients. We have demonstrated that single administration of some drugs approved for the other cancer, e.g. temozolomide or trabectedin, were effective on a chemotherapy-resistant osteosarcoma PDOX tumor. Some combinations of approved drugs, e.g. irinotecan-trabectedin, irinotecan-temozolomide, sorafenib-palbociclib, everolimus-sorafenib, and olaratumab-doxorubicin-cisplatinum, could regress chemotherapy-resistant osteosarcoma PDOX tumors. We have demonstrated efficacy of experimental therapy such as tumor-targeting Salmonella typhimurium A1-R and recombinant methioninase could eradicate cisplatinum-resistant lung metastasis in an osteosarcoma PDOX model, when combinations of these agents were administrated with cisplatinum. In an era of increasing promise of novel systemic treatment and precision oncology, PDOX models present a unique opportunity to provide osteosarcoma patients with specific and personalized therapy and novel treatment options.