AMPK is a cellular energy sensor that negatively regulates the mTOR signaling pathway. As mTOR plays critical roles in cell growth and tumorigenesis of renal cell carcinoma (RCC), we examined whether exogenous induction of AMPK activity exhibits inhibitory effects on growth and survival of renal cell carcinoma cells. Activation of AMPK by AICAR resulted in potent suppressive effects on RCC growth, while combinations of AICAR with statins were potent inducers of apoptosis in such cells. The effects of AICAR resulted from inhibition of mTOR and its effectors, resulting from induction of AMPK activity. Similar results on RCC cell growth were obtained when combinations of metformin with statins were examined. Importantly, studies to examine the effects of AICAR or metformin, alone or in combinations with statins, on anchorage-independent growth demonstrated potent suppressive effects on RCC tumorigenicity in vitro. Altogether, our studies demonstrate that AMPK plays critical regulatory roles in the regulation of growth of RCC cells and raise the prospect of future use of AMPK activators in the treatment of renal cell carcinoma in humans.