Interleukin (IL)-22 is a member of IL-10 family cytokines with various immunologic functions. As its name implies, IL-22 is known to be secreted mainly by Th22 cells, a recently discovered lineage of CD4+ T cells. Also, Th17, Th1, natural killer cells, γδT cells, and innate immune cells along with some nonlymphoid cells have been confirmed as secondary cellular sources of IL-22. Different cell types such as bronchial and intestinal epithelial cells, keratinocytes, hepatocytes, dermal fibroblasts, and tubular epithelial cells are affected by IL-22. Both pathologic and protective roles have been attributed to IL-22 in maintaining gut homeostasis and inflammation. According to the latest fast-growing investigations, IL-22 is significantly involved in various pathologies including allergic diseases, infection, autoimmunity, and cancer development. Regulating gut immune responses, barrier integrity, and inflammation is dependent on a diverse complex of cytokines and mediators which are secreted by mucosal immune cells. Several investigations have been designed to recognize the role of IL-22 in gastrointestinal immunity. This article tries to discuss the latest knowledge on this issue and clarify the potential of IL-22 to be used in the future therapeutic approaches of intestinal disorders including inflammatory bowel diseases and colon cancer.© 2020 International Union of Biochemistry and Molecular Biology.