Osteosarcoma is the most common primary tumor of bone and accounts for approximately 19% of all malignant tumors of bone. It is the third most common malignant tumor in teenagers. More than twenty years ago, the advent of a multidisciplinary approach that combined multi-agent chemotherapy and limb-sparing surgery greatly improved the survival rate of patients with osteosarcoma. Unfortunately, since that time, survival rates have not dramatically improved. To date, the most powerful predictors of outcome have remained the ability to detect metastatic disease at diagnosis and the histopathologic response of the tumor to preoperative chemotherapy. Presently, 80% of patients who do not have distant metastases at initial diagnosis will become long-term survivors. Unfortunately, this means that approximately 20% of patients who do not present with metastases at diagnosis will not survive. This group of patients appears to be resistant to current treatment as attempts to intensify therapy after surgery for patients with a poor histopathologic response has not significantly improved survival rates. It is these patients that are in the greatest need of additional clinically relevant markers for prognosis and who can be most helped by molecular analysis. While steady progress has been made in the identification of genetic alterations in osteosarcoma, no individual molecular marker has thus far been demonstrated to have a better prognostic significance in the treatment of osteosarcomas than the current clinical markers. Thus there is clearly a need to employ new comprehensive analysis technologies to develop significantly more informative classification systems and to identify new therapeutic targets.