T helper (Th) cells develop from naïve CD4⁺ T cells under lineage-specific culture conditions and are nominated by their lineage-specific cytokines. Th22 cells, new players in adoptive immune responses, are identified by the production of interleukin (IL)-22. Plenty of observations are obtained over the past few years indicating that IL-22 is produced by activated T cells including Th22 cells, Th17 cells, Th1 cells, innate lymphoid cells and some nonlymphocytes. IL-22 functions synergistically with IL-17 or tumor necrosis factor (TNF), however, it plays different roles by IL-22/IL-22 receptor signal transductions in pathologic processes, including inflammations, autoimmunity, tumor, and digestive organs damages. In this chapter, we focus on the biology of IL-22, the generation and regulation of Th22 cells, the possible signal pathways that involved in the functions of Th22 cells, as well as the relationship between Th22 cells and various diseases.