The identification of KIT as a critical driver in the pathogenesis of GI stromal tumor (GIST), and its subsequent inhibition with imatinib, have resulted in tremendous efforts to identify other potential therapeutic targets for the heterogeneous group of diseases known as sarcomas. Because of the rarity of sarcoma and the often limited number of patients per individual sarcoma subtype, clinical trials to date have often utilized unselected patient populations including multiple subtypes. Although this strategy increases the ease with which a particular trial may accrue patients, statistically significant therapeutic responses across an unselected patient population are often limited. Furthermore, in the absence of biologic correlatives, the identification of significant activity and subsequent interpretation of clinical trial results utilizing targeted therapies for this patient population have been challenging. However, hints have emerged, on the basis of preclinical and clinical observations, to suggest that certain targeted therapeutic approaches are appropriate in select histologic subtypes. This brief review will highlight data supporting the use of targeted therapy in both unselected and selected sarcoma patient populations.