Despite significant advancements in the diagnosis and treatment of osteosarcoma to date, overall survival has remained relatively constant for over 2 decades. The challenge in osteosarcoma stems from the extreme variability from one tumor to the next, making it unlikely that a single target approach would be able to address all or even a majority of patients. Awareness, education, and proper referral patterns serve to minimize avoidable errors in diagnosis and treatment. However, it is unlikely that these efforts alone will significantly improve survival outcomes. Modern multi-agent chemotherapy has resulted in the greatest improvement in overall survival to date, and it is very likely that future improvements in survival will arise from combination-targeted chemotherapy in addition to conventional treatment.