New medical strategies have emerged over the past decade for the treatment of advanced renal cell carcinoma based on the discovery of specific molecular abnormalities. However, molecular targeted therapeutics including anti-angiogenics have demonstrated significant limits (limited impact on overall survival, development of potential severe toxicities). We review the future directions for drug development based on specific interaction with cellular and extra-cellular pathways. Both von Hippel-Lindau alterations and high immunogenicity profile represent two remarkable characteristics identified in clear cell carcinoma. The new generation of anti-angiogenics (including HIF, Notch, or angiopoietin inhibitors) and recent developments in immunotherapy also provide opportunities to modify the prognosis of advanced renal cell carcinoma.