In this issue of the journal, we host a topic focused on the roles of human Forkhead-box (FOX) gene family members, including FOXN1, FOXP genes, and FOXO1, in the immune system. In the first review of the issue, Palamaro et al. focused their attention on the pivotal role of FOXN1 in T-cell development and the clinical implications of its mutation in humans. Dr Fleskens and Dr van Boxtel detailed the role of FOXP members in immune regulation. Concerning the roles of FOXP members in immune response, Vent-Schmidt et al. focused the attention on FOXP3. Passerini et al. highlighted the current knowledge on the involvement of FOXP3 in the development and function of Treg cells. Eventually, in the last review of this special issue, Szydłowski et al. focused on the role of FOXO1 in B-cell development and differentiation, paying particular attention to the role of PI3K-AKT signaling activation in development, differentiation, function, and homeostasis of B cells. Notably, studies on the role of FOX family members in immune response could be helpful to further investigate pathogenesis of immunological disease and to develop a novel therapeutics approach for human diseases.