Interleukin (IL)-22 is a cytokine that is involved in the modulation of tissue responses during inflammation. It is produced by immune cell subsets such as T cells, while the expression of its receptor is restricted to cells of non-hematopoietic origin, particularly epithelial cells. In the skin, IL-22 induces keratinocyte proliferation and epidermal hyperplasia, inhibits terminal differentiation of keratinocytes, and promotes the production of antimicrobial proteins. Although IL-22 was initially thought to be produced by T helper (Th)17 cells, IL-22 production can also occur in an apparently unique subset of cells, Th22 cells, which lack the ability to produce IL-17 and interferon-γ. Of note, Th22 cells, which express the skin homing chemokine receptors CCR4 and CCR10, reside in the normal skin and are enriched in the lesional skin of inflammatory skin diseases, indicating the importance of IL-22 in skin homeostasis and pathogenesis of skin diseases. Although a critical role of IL-22 was initially highlighted in psoriasis, a growing body of evidence indicates that this cytokine also plays a role in atopic dermatitis and other inflammatory skin diseases. Moreover, emerging experimental data suggest that IL-22 also participates in the pathophysiology of malignancies of the skin. In this review, recent findings regarding the expression, regulation, and function of the IL-22 pathway in various human skin diseases will be discussed. Considering the strong association between excess activation of the IL-22/Th22 pathway and human skin diseases, targeting this pathway may provide promising new therapeutic approaches.