IL-21 (another common gamma chain cytokine) that is produced primarily by CD4+ T cells of the TFH lineage has a range of functions, including the promotion of apoptosis, proliferation, and gain of effector function in B cells, T cells, NK cells, and DC. After BMT, TFH cells drive marginal zone B cell expansion and aberrant B cell development. These B cells produce alloantibodies in a Bruton's tyrosine kinase (BTK)–dependent manner, and these antibodies are now established as making a critical contribution to cGVHD. IL-21 also induces IL-10 production and can thus have both regulatory and proinflammatory roles, depending on the other cytokines present. IL-21R deficient animals and specific blocking antibodies have been used to assess the role of IL-21 in GVHD, confirming it has a pathogenic role in the GI tract (with receptor-deficient animals experiencing less GI-specific GVHD). The use of IL-21 blocking mAb used in a xenogeneic mouse model (with NOD/SCID/γc−/- recipients) has demonstrated a decrease in CD8+ T cells and an increased proportion of Tregs. This group also demonstrated local protein expression of IL-21 in the GIT and skin, but not serum. Neutralization of IL-21 represents a promising therapeutic strategy to prevent and treat cGVHD that now requires investigation in a clinical study.