In both Crohns disease (CD) and ulcerative colitis (UC), the major forms of inflammatory bowel diseases (IBD) in humans, the pathologic process consists of an aberrant local immune response to components of the bacterial microflora, due to abnormally strong effector cell activity that is poorly controlled by counter-regulatory mechanisms. There is also evidence that mucosal immune cells actively interact with non-immune cells to promote tissue damage, and that cytokines are essential mediators of this cross-talk. Interleukin-21 (IL-21), the latest member of the common γ-chain-dependent cytokine family, is a product of activated CD4+ T cells and natural killer T cells. IL-21 is produced in excess in CD tissue, where it helps sustain the ongoing Th1 inflammation. High IL-21 production occurs also in the inflamed colon of most patients with UC, a disease that is not associated with a marked Th1 cell response. This suggests that, in the gut, IL-21 can modulate additional inflammatory pathways other than enhancing Th1 cell immunity. Indeed, IL-21 stimulates the secretion of extracellular matrix degrading enzymes by fibroblasts, and of the T cell chemoattractant, MIP-3α, by epithelial cells. These data collectively indicate that IL-21 is a mediator of the chronic inflammatory response in CD and UC, and suggest that IL-21 may be an emerging therapeutic target in IBD.