IL-21 is a 17 kD member of the common gamma chain family of cytokines and mainly produced by CD4+ T subsets, including Th17, follicular helper T cells (TFH), Th2, memory CD4+ T cells, and NKT cells. IL-21 signals through a heterodimeric receptor complex containing IL-21R and the common cytokine receptor gamma chain (CD132). IL-21 has effects on T, B, NK, and myeloid cells, regulates both humoral and cell-mediated immunity. It has been reported that IL-21 is able to enhance the expansion of Th17 cells via the induction of IL-23R, cooperates with IL-7 or IL-15 to promote CD8+ T cell expansion. IL-21 is also known to regulate Ig production by driving the differentiation of B cells to antibody-producing plasma cells and involving in the development of follicular helper T cells (TFH). In addition, IL-21 exerts negative effect on lymphoid and myeloid cells, including induction of B cell apoptosis and inhibition of dendritic cell maturation and function. The type of actions mediated by IL-21 is presumably determined by its biological context, specific activation state of the target cells, as well as the cytokine milieu. IL-21/IL-21R system is involved in the pathogenesis of various autoimmune diseases and anti-tumor effects.