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The immune system is composed of the closely interacting innate and adaptive effector systems, and it serves to eliminate almost all types of pathogens as well as some malignancies. Whereas the innate arm of the immune system provides an immediate, but nonspecific, form of defense against pathogens, it is the system’s adaptive response, which is mediated by B and T lymphocytes, that assures antigen specificity and immunological memory, albeit after a delay of several days. The vast majority of T cells are formed in the thymus, which provides cell-surface and soluble ligands that are essential for T lineage commitment and differentiation. Among the pathways that are important for the de novo formation of T cells, signals that engage phosphatidylinositol 3-kinases (PI3Ks) are of particular importance, which is a finding consistent with a physiological role of PI3K signaling in cell differentiation in many different tissues. Moreover, uncontrolled activation of PI3K in thymocytes is associated with the formation of tumors, which highlights the requirement for a precise control of PI3K activity. In this Review, including two figures and 174 references, we discuss the importance of the PI3K-phosphoinositide–dependent protein kinase (PDK1)–protein kinase B (PKB) signaling pathway for the development of both normal and malignant thymocytes, and we outline the potential to target this pathway for therapeutic interventions.