Although osteosarcoma is a relatively rare neoplasm, it does represent the most common bone malignancy of childhood with an incidence of 4-5 per million population. Diagnosis and classification of osteosarcoma relies on correlation of biopsy findings with imaging studies. While molecular findings continue to be of limited value in the diagnosis of osteosarcoma, researchers' understanding of the molecular pathogenesis of this neoplasm and the molecular pathways involved has increased significantly in recent years. These findings do contribute to one's understanding of tumor prognosis, and may in the future yield important information for directed therapy. The understanding of these processes has been enhanced through the study of syndromes associated with an increased risk of osteosarcoma, with studies of sporadic osteosarcoma, and with research involving animal models. This chapter reviews specific tumor suppressor genes, oncogenes, and molecular pathways which have been implicated in the development and progression of osteosarcoma. © 2010 Elsevier Inc. All rights reserved.