Osteosarcoma is the most frequent primary bone tumor and occurs mainly in young patients (average age: 18 years). No evolution of the survival rates has been recorded for two decades in response to current treatment, associating often toxic and badly tolerated cures of chemotherapy (given a significant rate of bad responders) with preserving surgery. Among the proposed innovative strategies, immune-based therapy, antiangiogenesis agents, tumor-suppressor or suicide gene therapy, or anticancer drugs not commonly used in osteosarcoma are presented. A further strategy is to target the tumor microenvironment rather than the tumor itself.