Inhibitors ofphosphatidylinositol 3-kinase (PI3-K) are in active clinical development for the therapy of patients with metastatic renal cell carcinoma (RCC).This follows on the heels of the recent demonstration of clinical activity and subsequent FDA approval of two allosteric inhibitors of mammalian target of rapamycin (mTOR), a kinase regulated downstream of PI3-K, in patients with advanced RCC.However, while there is optimism for these novel agents in RCC, it remains likely that only a subset of patients will derive substantial clinical benefit and efforts must be focused on mechanisms of resistance as well as potential rationale combinations with other molecularly targeted agents.