Although osteosarcoma (OS) is a rare malignancy, it is ranked among the leading causes of cancer-related death in the pediatric age group. The cancer's low prevalence and its large tumor heterogeneity make it difficult to obtain meaningful progress in patient survival. In this review we present an overview of current clinical trials which largely focus on stimulation of the immune system or rely on the inhibition of kinases such as Src and mTOR. The potential efficacy of tumor-targeted TNFalpha is discussed, as well as the importance of preclinical validation of new targets. To improve the success of future clinical trials, clinicians and basic researchers need to intensify their exchange. Finally, a case is made for individualized treatment of OS patients, based on interdisciplinary cooperation in dedicated Sarcoma Centers.