The Foxo subfamily of forkhead (Fox) transcription factors are mammalian homologues of the Caenorhabditis elegans DAF-16 longevity gene, and play key roles in cellular and organism survival, death, proliferation and metabolism. A growing body of evidence indicates that Foxo proteins furthermore play critical roles in immune cell homeostasis, modulating inflammation in some disease states such as inflammatory arthritis and systemic lupus erythematosus (SLE), via fundamental roles in T cells, B cells, neurophils and other myeloid lineages. This review summarizes current knowledge of the Foxo family members in general and in immunity, including their potential use as therapeutic targets.