In both Crohn's disease (CD) and ulcerative colitis, the pathologic process is almost certainly driven by an aberrant local immune response directed against normal components of the bacterial microflora. Mucosal immune cells interact with nonimmune cells such as epithelial cells and fibroblasts to promote tissue damage; cytokines are essential mediators of this cross talk. Accumulating evidence now suggests that interleukin-21 (IL-21), the newest member of the common gamma-chain-dependent cytokine family, is a key component of the inflammatory cascade. IL-21 is highly produced by activated CD4+ lymphocytes in the inflamed gut of patients with CD, where it contributes to sustaining the ongoing Th1 inflammation. IL-21 also increases the secretion of extracellular matrix-degrading enzymes by fibroblasts and of MIP-3alpha by epithelial cells. Two other cytokines, IL-27 and IL-32, may also be important in the inflammatory pathways that operate in IBD.