IL-22 is an IL-10 family cytokine member that was recently discovered to be produced by Th17 cells. Current studies have revealed that IL-22 targets cells of the digestive, skin, and respiratory organ systems and plays an important role in mucosal immunity. The IL-22 receptor (IL-22R) is expressed exclusively in these tissues, thereby allowing the cytokine to mediate epithelial innate immunity in response to a variety of pathogens. Although recent studies have shown the importance of IL-22 in host defense against Gram-negative bacterial organisms (in gut and lung), there is evidence that IL-22 also plays a role in autoimmune disease, such as psoriasis. IL-22 therefore, not unlike other cytokines, has complex pro-inflammatory, anti-inflammatory, and autoimmune effects which continue to be under further investigation. This review will focus on what is known about IL-22 and its function in mucosal host defense.