Cytokines play critical roles in regulating the development, survival, differentiation, and function of immune cells. Cytokines exert their function by binding specific receptor complexes on the surface of immune cells and activating intracellular signaling pathways, thereby resulting in induction of specific transcription factors and regulated expression of target genes. While the function of cytokines is often fundamental for the generation of robust and effective immunity following infection or vaccination, aberrant production or function of cytokines can underpin immunopathology. IL-21 is a pleiotropic cytokine produced predominantly by CD4+ T cells. Gene-targeting studies in mice, in vitro analyses of human and murine lymphocytes, and the recent discoveries and analyses of humans with germline loss-of-function mutations in IL21 or IL21R have revealed diverse roles of IL-21 in immune regulation and effector function. This review will focus on recent advances in IL-21 biology that have highlighted its critical role in T cell-dependent B cell activation, germinal center reactions, and humoral immunity and how impaired responses to, or production of, IL-21 can lead to immune dysregulation.