The interleukin (IL)-10 family of cytokines comprising IL-10, IL-19, IL-20, IL-22, IL-24, IL-26, IL-28α, IL- 28β, and IL-29 uses receptors of the cytokine receptor family class 2. Here we review the current knowledge about IL-22 receptor-α2 (IL-22Rα2) which is the first known soluble receptor of that cytokine family. The human IL-22Rα2-encoding gene includes seven exons and is located on chromosome 6 between the genes for interferon-γ receptor-1 and IL-20 receptor- 1. The products of this gene are three different mRNA splice variants. The genes for the mouse and rat IL-22Rα2 have a very similar genomic location and structure to those in humans, although they lack the human exon 4 counterpart and produce only one variant which corresponds to the human variant 2. Irrespective of the species and splice variant, IL- 22Rα2 lacks any sequence for a transmembrane or an intracellular part, and is a secreted protein. It is particularly expressed in the placenta, the mammary glands, and the lymph nodes but also in the gastrointestinal system, the lungs, the skin, and other lymphatic organs. It seems, however, that the variants 3 and 1 are more restricted in their expression. Variant 2 binds to and inhibits the activity of IL-22 in vitro, whereas the specificity of variants 3 and 1 has not been identified. The discovery of IL-22Rα2 represents a first step towards understanding the regulatory network regarding the action of IL-22 and perhaps of other members of the IL-10 family. It also may open up new ways for targeting the action of these cytokines for therapeutic interests.