Current therapy for osteosarcoma successfully treats 60% to 70% of patients. Attempts to identify patients who will respond poorly to therapy has focused on the use of new biologic markers or microarray cluster analysis. New potential therapeutic targets, including growth factors, chemokines, transcription factors, and angiogenic factors, are being evaluated for their roles in osteosarcoma. These new targets may provide mechanisms to treat the patients who would respond poorly to standard therapy.