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In the past decade, progress has been made in the development of targeted therapies for advanced renal cell carcinoma (RCC). However, as multiple therapeutic choices become available to clinicians, we currently lack effective indicators that allow physicians to choose the best treatment option for specific patients. For approved targeted therapies, potential molecules that could indicate drug effectiveness in a specific tumor follow naturally from both the therapeutic mechanism and the previously elucidated tumor biology. However, in advanced RCC, the use of these molecules as biomarkers for treatment selection has shown equivocal results and requires further investigation. In addition to looking at specific molecular targets, subclassification of tumors based on their molecular characteristics may also allow stratification of patients based on therapeutic benefits, providing information for treatment selection. Furthermore, the continued development of such tumor classification schemes will hopefully uncover other molecular targets that warrant development as future RCC therapies. The use of molecular classification of patients' tumors for treatment selection will provide the opportunity to increase the effectiveness of currently available therapies for advanced RCC and to judiciously pursue promising options for future RCC therapies.