Interleukin (IL)-21 is a member of a family of cytokines that includes IL-2, IL-4, IL-7, IL-9, and IL-15, all of which utilize a common γ chain in their individual receptor complexes for delivering intracellular signals in their target cells. IL-21 is produced by CD4+ T-cells, in particular follicular T-helper cells, and is critically important in the regulation and maintenance of T cells and B cells in innate and adaptive immunity. The effects of IL-21 are pleiotropic because of the broad cellular distribution of the IL-21 receptor, and it plays a critical role in T cell-dependent and -independent human B cell differentiation for generating humoral immune responses. This article reviews the current knowledge about the importance of IL-21 and IL-21 receptor interaction in human B cell responses, immune defects of B cells and IL-21 in HIV infection, and the potential applicability of IL-21 in vaccines/immunotherapeutic approaches to augment relevant immune responses.