Interleukin‐21 (IL‐21), a cytokine produced by various subsets of activated CD4+ T cells, regulates multiple innate and adaptive immune responses. Indeed, IL‐21 controls the proliferation and function of CD4+ and CD8+ T lymphocytes, drives the differentiation of B cells into memory cells and Ig‐secreting plasma cells, enhances the activity of natural killer cells and negatively regulates the differentiation and activity of regulatory T cells. Moroever, IL‐21 can stimulate nonimmune cells to synthesize various inflammatory molecules. Excessive production of IL‐21 has been described in many human chronic inflammatory disorders and there is evidence that blockade of IL‐21 helps attenuate detrimental responses in mouse models of immune‐mediated diseases. In this article we briefly review data supporting the pathogenic role of IL‐21 in immune‐inflammatory pathologies and discuss the benefits and risks of IL‐21 neutralization in patients with such diseases. © 2013 BioFactors, 39(4):368–373, 2013