Interleukin 21 (IL-21) is produced by activated CD4(+) T cells. The IL-21R shares the common receptor gamma-chain with IL-2, IL-4, IL-7, IL-9, and IL-15, is widely expressed on immune cells, and mediates a variety of effects on the immune system. IL-21 enhances the proliferation, antigen-induced activation, clonal expansion, IFN-gamma production, and cytotoxicity of NK cells and T cells. The antitumor actions of IL-21 have been variously attributed to NK cell and CD8(+) T cell cytotoxicity, CD4(+) T cell help, NKT cells, and the antiangiogenic properties induced by IFN-gamma secretion. In clinical trials IL-21 has been well tolerated and induces a unique pattern of immune activation. IL-21 is therefore an excellent candidate for use in immune therapy.