Upon encounter with antigen, CD4⁺ T cells differentiate into effector T_h subsets with distinctive functions that are related to their unique cytokine profiles and anatomical locations. One of the most important T_h functions is to provide signals to developing B cells that induce specific and appropriate antibody responses. The major CD4⁺ T cell subset that helps B cells is the T follicular helper (T_FH) cell, whose expression of the chemokine receptor CXCR5 [chemokine (C–X–C motif) receptor 5] serves to localize this cell to developing germinal centers (GCs) where it provides instructive signals leading to Ig class switching and somatic mutation. T_FH cells produce high levels of IL-21, a cytokine that is critical for GC formation and also for the generation of T_FH cells. Although T_FH cells have been found to produce cytokines characteristic of other T_h subsets, they represent a distinct lineage whose development is driven by the transcription factor B-cell CLL lymphoma-6 (BCL6). Consistent with their critical role in the generation of antibody responses, dysregulated T_FH function has been associated with the development of systemic autoimmunity. Here, we review the role of IL-21 in the regulation of normal T_FH development and function as well as in progression of autoimmune responses.