IL-22 is a Th17 T-cell-associated cytokine that is highly expressed during chronic inflammation. IL-22 receptor expression is absent on immune cells, but is instead restricted to the tissues, providing signaling directionality from the immune system to the tissues. Through Stat3 signaling, IL-22 induces a variety of proliferative, anti-apoptotic, and anti-microbial pathways. IL-22 is bi-functional with both pro-inflammatory and protective effects on tissues depending on the inflammatory context. The cytokine plays a role both in the host response against extracellular pathogens and in the inflammation associated with autoimmune diseases. Therapeutics targeting IL-22 therefore may have promise for treating various chronic inflammatory diseases.