In the quest for personalized medicine, only a few biological parameters are routinely used to select patients prior to the initiation of anticancer targeted therapies, including mTOR inhibitors. Identifying biological factors that may predict efficacy or resistance to mTOR inhibitors represents an important challenge since rapalogs may exert antitumor effects through multiple mechanisms of action. Despite the fact that no such a factor is currently available, several molecular patterns are emerging, correlating with sensitivity and/or resistance to rapalogs. While activation of the phosphatidylinositol 3 kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway, overexpression of cyclin D1, and functional apoptosis seem to sensitize tumor cells to rapalogs, Bcl2 overexpression or KRAS mutations are reported to be associated with resistance to mTOR inhibitors in several preclinical models. Translational research aimed at validating those parameters in clinical trials is ongoing.