Interleukin (IL)-21 is a member of the γ chain-receptor cytokine family along with IL-2, IL-4, IL-7, IL-9, and IL-15. The effects of IL-21 are pleiotropic, owing to the broad cellular distribution of the IL-21 receptor. IL-21 is secreted by activated CD4 T cells and natural killer T cells. Within CD4 T cells, its secretion is restricted mainly to T follicular helper (Tfh) cells and Th17 cells to a lesser extent. Our research focus has been on the role of IL-21 and more recently of Tfh in immunopathogenesis of HIV infection. This review focuses on first the influence of IL-21 in regulation of T cell, B cell, and NK cell responses and its immunotherapeutic potential in viral infections and as a vaccine adjuvant. Second, we discuss the pivotal role of Tfh in generation of antibody responses in HIV-infected persons in studies using influenza vaccines as a probe. Lastly, we review data supporting ability of HIV to infect Tfh and the role of these cells as reservoirs for HIV and their contribution to viral persistence.