Recent studies have highlighted a fundamental role for Forkhead box O (Foxo) transcription factors in immune system homeostasis. Initial reports designed to dissect function of individual Foxo isoforms in the immune system were based on in vitro overexpression systems, and these experiments suggested that Foxo1 and Foxo3 are important for growth factor withdrawal-induced cell death. Moreover, Foxo factors importantly regulate basic cell cycle progression, and so the implication was that these factors may control lymphocyte homeostasis, including a critical function in the termination and resolution of an immune response. Most recently, cell-type-specific loss mutants for the different Foxo isoforms have revealed unexpected and highly specialized functions in the control of multiple cell types in the immune system, but they have yet to reveal a role in cell death or proliferation. This review will focus on the recent advances made in the understanding of the many ways that Foxo factors regulate the immune system, including a discussion of how the specialized versus redundant functions of Foxo transcription factors impact immune system homeostasis.