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Mammalian target of rapamycin (mTOR) is a key regulator of eukaryotic cell growth. In particular, mTORC1, one of the two complexes that contain mTOR, is involved in the regulation of protein synthesis, proliferation, cell cycle and autophagy. Hyperactivation of the mTOR signaling pathway is observed in human cancer. A variety of approaches including deletion analysis, yeast genetic screens and mining of human cancer genome databases were taken that resulted in the identification of activating mutations of TOR. These studies suggest that the FAT, FRB and kinase domains are the three regions of TOR where activating mutations can be identified. Within the kinase domain, the mutations are clustered in three hot spots that are all located in the kinase active site that was deduced by the alignment with PI3K. One of the hot spots corresponds to the region where PI3K oncogenic mutations have been identified. These results are beginning to provide important insights into the mechanism of activation of mTOR.