Even in tumor centers using established protocols, the survival rate of patients with osteosarcoma has not improved significantly in recent years. Novel therapies are urgently needed as an adjunct to conventional treatment modalities, to reduce the dose and subsequent toxicity associated with current chemotherapy, improve local disease control, prevent development of metastases, and offer an alternative treatment for those tumors that are poorly responsive to chemotherapy. Anti-angiogenic therapy currently holds great potential in conjunction with conventional treatment modalities for osteosarcoma. Specifically, anti-angiogenic factors derived from cartilage, a natural barrier to osteosarcoma invasion, may have important therapeutic applications in osteosarcoma.