The PI3K/AKT/mTOR signaling network is activated in a large fraction of human cancers and is a target for an increasing number of therapeutics. This pathway is also strongly triggered by stimulation of antigen receptors and costimulatory molecules, and controls diverse aspects of lymphocyte proliferation and differentiation. Interestingly, both gain- and loss-of-function mutations in PI3K genes can cause immunodeficiency in humans, phenotypes that are recapitulated in mouse models. Activated PI3Kdelta syndrome (APDS) is an immunodeficiency syndrome that is also associated with lymphoproliferation and increased frequency of lymphoid malignancies. In this presentation, I will provide background to explain the conceptual basis to explain these complex phenotypes. I will then discuss what is currently known about the impact of PI3K pathway inhibitors on normal immune function and on disease symptoms in APDS. Lastly, I will present data from my laboratory that highlights the role of the translation initiation complex eIF4F as an mTOR effector and potential therapeutic target in lymphoid malignancy and autoimmunity.