Interleukin 21 (IL-21) is a four α-helix bundle cytokine and closely related to IL-2, IL-4, and IL-15. IL-21 expression is restricted to activated CD4+ T helper cells and NKT cells. Among T helper subsets, IL-21 is strongly produced by follicular T helper cells and TH17 cells, where IL-21 serves as an autocrine regulator and seems to sustain TH17 development. The functional receptor for IL-21, composed of the IL-21 receptor- and the common γ-chain, is expressed on various hematopoietic cells including T, B, NK, and dendritic cells. Accordingly, IL-21 exerts pleiotropic effects on both cellular and humoral immune responses, such as stimulation of lymphocyte proliferation, promotion of CD8+ T cell and NK cell cytotoxicity, and differentiation of B cells into plasma cells. Important roles for IL-21 have been proposed with regard to its anti-tumor activity and for the development of autoimmune diseases.