Osteosarcoma is the most common malignant bone tumor in children and adolescents. Although pathologic characteristics of this disease are clear and well established, much remains to be understood about this tumor, particularly at the molecular signaling level. Secreted signaling molecules of the Wnt family have been widely investigated and found to play a central role in controlling embryonic bone development, bone mass, and postnatal bone regeneration. A variety of studies also suggest that Wnt signaling pathway is closely associated with bone malignancies, including breast or prostate cancer induced bone metastasis, multiple myeloma, as well as osteosarcoma. Here, we provide an overview of the role of Wnt signaling pathway in osteosarcoma development and progression, highlighting the aberrant activation of Wnt pathway in this bone malignancy. We also discuss the potential therapeutic applications for the treatment of osteosarcoma targeting Wnt pathway. J. Cell. Biochem. 115: 625–631, 2014. © 2013 Wiley Periodicals, Inc.