The treatment of sarcoma urgently requires new, innovative therapeutic strategies. The most recent improvements in the cure of patients with localized disease have been achieved by dose-intensification, in turn paying the price of acute severe toxicity and secondary malignancies. Keeping side-effects to a minimum is an important goal for pediatric patients and this may be achieved by combining standard cytotoxic chemotherapy with targeted approaches. In addition, after first-line therapy, very limited treatment options remain for patients with disease progression, who, like patients with metastasis at diagnosis, are in urgent need of more effective drugs. The present review highlights key examples of target identification in bone sarcomas, including chimeric oncoproteins, insulin-like growth factor receptor (IGF-IR), and tumor/microenvironment interactions. The review identifies questions and concerns that still need to be addressed before proceeding to safe clinical trials with agents against these promising new targets.