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Approximately one-fourth of osteosarcoma patients have metastases at presentation. The best treatment options for these patients include chemotherapy, surgery, and radiotherapy; however, the optimal scheme has not yet been defined. Standard chemotherapy for osteosarcoma metastatic at presentation is based on high-dose methotrexate, doxorubicin, and cisplatin (the MAP regimen), with the possible addition of ifosfamide. Surgical treatment continues to be fundamental; complete surgical resection of all sites of disease (primary and metastatic) remains essential for survival. In patients whose tumors do not respond to neoadjuvant chemotherapy, early surgical resection of the primary tumor with limb-salvage surgery or amputation and multiple metastasectomies, if feasible, after the completion of adjuvant chemotherapy is a reasonable option, as the reduction of the tumor volume could probably increase the effect of chemotherapy. Advanced radiotherapy techniques, such as carbon ion radiotherapy and stereotactic radiosurgery, and molecular targeted chemo-therapy with drugs such as pazopanib or apatinib have improved the dismal prognosis, especially for patients who are medically inoperable or who refuse surgery. Given that the presence of metastatic disease at diagnosis of a patient with osteosarcoma is a poor prognostic factor, a multidisciplinary approach by surgeons, medical oncologists, and radiotherapists is important. [Orthopedics. 2020;43(5):e345-e358.].