The primary bone malignancy osteosarcoma (OS) is a painful health burden, of which treatment remains a challenging problem. Identification of specific tumor biomarkers may help to investigate and develop the novel effective therapeutic approaches that have specific molecular target for the treatment of patients with OS. Osteopontin (OPN), a phosphorylated glycoprotein, is involved in many biological processes, such as biomineralization, bone remodeling and immune responses and has recently been reported to be associated with OS pathogenesis. Interestingly, both of the up- and down-regulation of OPN are involved in OS. During OS development, genetic or epigenetic disruption causes reduced expression of RUNX2 and OPN through the up-regulation of notch signaling pathway, leading to the development of OS. On the other hand, during hypoxic condition, upregulation of OPN induces the glucose uptake into hypoxic OS cells which is responsible for the OS cell proliferation and drug resistance. Recent evidences show that targeting OPN might be an important tool in OS therapeutics. This review has focused on the association of abnormal OPN expression with the pathogenesis of OS, the efficiency of OPN as a diagnostic tool for OS and the therapeutic aspects of OS by targeting OPN.