Pancreatic cancer is a leading cause of cancer-related death in the western world, and in most patients, current chemotherapies have negligible survival benefit. Evaluation of targeted therapies, however, is a relatively recent development. Paradoxically, mutations in KRAS, and in genes involved in one if its major effector pathways, the PI3K/Akt pathway, are often found simultaneously in human tumors. Accounting for this, we have recently found that activated PI3K/Akt signaling results in a weak senescence that actually impairs the stronger Ras-induced senescence. We showed that loss of Pten and thus activation of PI3K/Akt/mTOR signaling leads to acceleration of PDAC progression in mouse. Similarly, in humans, activation of PI3K/Akt/mTOR signaling correlated with poor patient survival. Importantly, these patients represent a discrete subpopulation of this disease in which PI3K/Akt/mTOR inhibitors might be effective. Reactivating senescence has recently emerged as a realistic outcome of cancer therapy. Clearly, promising treatments may work only in certain tumor subsets, or only as part of combinatorial approaches. Thus, careful consideration should be taken before selecting preclinical models and patient populations in which to test new agents.