Normal cells have multiple functional signaling pathways. These signaling pathways exhibit a complex array of cross connections. When a specific signaling event is acutely inhibited, normal cells likely have multiple mechanisms available to bypass the effects of the blockade. Indeed, the lack of phenotype or modest phenotype in many knockout mice is compatible with this model. Alternatively, normal cells may be able to enter a resting state when specific signaling pathways are inhibited. In the addiction or genomic instability model, the genomic instability that is necessary for tumor initiation and progression may contribute to a loss of alternative signaling pathways. When a cell is driven by a specific molecular event, there may be little selective pressure to maintain additional signaling pathways contributing to the loss. Thus acute inhibition of the driving pathway with molecular therapeutics may result in growth inhibition and apoptosis. In the proapoptotic model, growth stimuli may both induce proapoptotic and antiapoptotic signals. This may also explain the counterintuitive increase in proapoptotic molecules in multiple tumors. In the presence of signal transduction inhibitors, production of both antiapoptotic or proapoptotic signals is blocked. If the proapoptotic signal is long-lived or irreversible, the tumor cell would then undergo apoptosis. This model is compatible with the observation that introduction of multiple different oncogenes renders cells more sensitive to inhibitors of those oncogenes than parental cells. Indeed as discussed herein, introduction of activated PI3K or AKT renders cells sensitive to the effects of CCI-779 and in the case of PI3K, LY294002. These differential effects may provide the therapeutic index that allows molecular therapeutics to be successful in cancer management.