Allosteric inhibitors of the kinase mammalian target of rapamycin (mTOR) have demonstrated significant clinical activity in patients with advanced renal cell carcinoma (RCC). Unfortunately, substantial clinical responses to these rapalogues are seen only in a subset of patients with advanced RCC. Preclinical studies have identified multiple theoretical shortcomings of the rapalogues, and numerous novel agents directed against the phosphatidylinositol 3-kinase/Akt/mTOR pathway, which address many of these shortcomings, are in active clinical development. In this review, we discuss the preclinical and clinical experience with the rapalogues in RCC, potential mechanisms of resistance to the rapalogues, and the progress in the clinical development of novel agents directed against the phosphatidylinositol 3-kinase/Akt/mTOR pathway.