Osteosarcoma is the most common primary malignant bone tumor in children and adolescents. Despite significant clinical improvements over the past several decades through the use of combination chemotherapy and surgery, patients with metastatic or recurrent disease continue to have a very poor prognosis. Therefore, there is a continued need to study and understand the basic biology of osteosarcoma in order to devise more targeted and rational therapeutic strategies and ultimately to improve survival for these patients. This article reviews several aspects of osteosarcoma biology where data exist to suggest that specific pathways may play a role in the pathogenesis of this tumor. These areas include host genetic predispositions, tumor cytogenetics, molecular genetics (including the Rb, p53, RECQ helicase, and telomere pathways), and metastatic factors (ezrin, annexin 2, chemokine receptor 4, Fas/FasL pathways) that may contribute to both the initiation and the progression of tumor formation. Understanding the mechanisms of and interactions between the various molecular pathways that play a role in osteosarcoma pathogenesis may eventually lead to a more rational strategy for devising therapies targeted specifically toward these pathways.