The mammalian target of rapamycin (mTOR) represents a critical hub for the regulation of different processes in both normal and tumor cells. Furthermore, it is now well established the role of mTOR in integrating and shaping different environmental paracrine and autocrine stimuli in tumor microenvironment (TME) constituents. Recently, further efforts have been employed to understand how the mTOR signal transduction mechanisms modulate the sensitivity and resistance to targeted therapies, also for its involvement of mTOR also in modulating angiogenesis and tumor immunity. Indeed, interest in mTOR targeting was increased to improve immune response against cancer and to develop new long-term efficacy strategies, as demonstrated by clinical success of mTOR and immune checkpoint inhibitor combinations. In this chapter, we will describe the role of mTOR in modulating TME elements and the implication in its targeting as a great promise in clinical trials.