Interleukin-21 is the most recently discovered member of the type-I cytokine family. Structurally, IL-21 shows homology to IL-2, IL-4, and IL-15 proteins. IL-21 shares the common gamma-chain with the other three cytokines but, in addition, binds to a unique IL-21Ralpha chain, and activates the JAK/STAT pathway. IL-21 is mainly produced by activated T-cells but targets a broad range of lymphoid and myeloid cells of the immune system and therefore is able to regulate innate and acquired immune responses. This review intends to give the reader an overview of the recent findings concerning the biology of IL-21 and its physiological role in immunity, infection, and cancer.