The major goals of translational research in osteosarcoma entail the identification of prognostic factors and therapeutic targets. Given the relevance of epidermal growth factor receptor pathway to breast cancer and the finding that HER-2 was expressed in a proportion of osteosarcoma, it was reasonable to investigate this pathway further. Investigations of HER-2 in osteosarcoma have led to the publication of numerous conflicting reports with regard to the level and prognostic value of HER-2 expression, which are reviewed and discussed. Numerous lessons provided by this research experience are described. This pathway has also been explored as a therapeutic target with at least one study of trastuzumab for the treatment of osteosarcoma completed. Other studies utilizing alternative approaches to target the HER-2 receptor for the treatment of osteosarcoma have been considered.