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Osteosarcoma is a challenging disease requiring multidisciplinary management in expert centers for optimal outcome. There are no current international protocols or guidelines specific for pediatric and adolescent osteosarcoma. The European Standard Clinical Practice (ESCP) project is a collaboration between ERN PaedCan and SIOP Europe’s Clinical Trial Groups to develop approved clinical recommendations reflecting current best practice. This manuscript is a summary of the full ESCP guideline for patients with osteosarcoma. The manuscript provides evidence graded recommendations for diagnosis, staging, management, response evaluation and follow-up. The methodology as defined in the standard operating procedures of the European Society for Medical Oncology (ESMO) was applied. Experts of the Fight OsteoSarcoma Through European Research (FOSTER) consortium contributed. In summary, the ESCP provides guidance on low-grade, but has a focus on high-grade osteosarcoma. In high-grade osteosarcoma the outcomes of most recent trials for clinical subgroups (e.g., metastatic vs. non-metastatic, resectable vs. non-resectable) are discussed, for treatment-naïve as well as for recurrent/refractory disease. An overview of current evidence also highlights the need for further therapeutic development as patients with primary metastatic or recurrent/refractory high-grade osteosarcoma still have a poor prognosis. Intensified collaborative research is identified as a prerequisite to increase survival and to limit long-term toxicities.