The phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway is a key signaling pathway that has been linked to both tumorigenesis and resistance to therapy in prostate cancer and other solid tumors. Given the significance of the PI3K/Akt/mTOR pathway in integrating cell survival signals and the high prevalence of activating PI3K/Akt/mTOR pathway alterations in prostate cancer, inhibitors of this pathway have great potential for clinical benefit. Here, we review the role of the PI3K/Akt/mTOR pathway in prostate cancer and discuss the potential use of pathway inhibitors as single agents or in combination in the evolving treatment landscape of castration-resistant prostate cancer.