Cytokines have a decisive role in initiating and shaping pathologic responses in patients with various immune-inflammatory diseases. Recent studies indicate that interleukin (IL)-21, a cytokine produced mostly by activated CD4+ T cells, participates in the tissue damage in various tissues, owing to its ability to regulate the function of immune and non-immune cells. For instance, IL-21 controls the differentiation and functional activity of T cells, B cells and NK cells, limits the differentiation of inducible regulatory T cells (Tregs), and makes T cells resistant to the Treg-mediated immunesuppression. It also stimulates epithelial cells and fibroblasts to produce inflammatory mediators. Here, we focus on data supporting the pathogenic role of IL-21 in human inflammatory diseases and discuss pre-clinical studies that suggest that neutralization of IL-21 in vivo could be a new biological therapy to combat immune-mediated pathologies, such as inflammatory bowel diseases, diabetes, rheumatoid arthritis and systemic lupus erythematosus.