Ewing sarcoma represents the second most common bone tissue malignancy in adolescents and young adults. Considerable progress in both local therapy (surgery or radiation therapy) as well as systemic chemotherapy during the past 4 decades has raised the 5-year survival rate from around 10% to 55-65%. However, survival for the 25% of patients with metastatic disease at diagnosis remains poor: less than a quarter survive beyond 5 years. Moreover, a survival plateau seems to have been reached with conventional therapies, suggesting that novel approaches are needed especially for high-risk disease. Identification and well-designed testing of novel agents is crucial for this challenging group of patients. Ewing’s sarcoma is defined as a bone tumor which may occur at any site within the skeleton but affects preferentially the trunk and the diaphysis of long bones. It arises less commonly in extraskeletal soft tissues (15%). Bone lesions from primary or secondary (metastases) tumors are characterized by extensive bone lesions, mainly due to osteolysis. Osteoclast activation and subsequent bone resorption is responsible for the clinical features of bone tumors including pain, vertebral collapse and spinal cord compression. Therefore, drugs which target the bone resorbing cells, i.e. osteoclasts, may represent promising agents in an adjuvant setting for the treatment of bone tumors. Two main drug families will be described more in detail in this review: the bisphosphonates (BPs) on one hand and drugs targeting the pro-resorbing cytokine Receptor activator of NF-kappa B Ligand (RANKL) [osteoprotegerin (OPG), RANK-Fc, RNAi targeting RANKL expression] on the other hand.