Recent advances from our own group and others have defined a novel PML/PTEN/Akt/mTOR/FoxO signaling network, and highlighted its critical importance in oncogenesis as well as in the functional regulation of normal stem cell and cancer-initiating cell (CIC) biology. These findings are of great importance in cancer therapy in view of the fact that this network is amenable to pharmacological modulation at multiple levels. The integrated analysis of these data allows us to propose a new provocative working model whereby the aberrant superactivation of Akt/mTOR signaling elicits built-in cellular fail-safe mechanisms that could be effectively utilized for cancer treatment to extinguish the CICs pool. In this review, we will discuss these recent findings, this working model, and their therapeutic implications.