This study investigates the role of interleukin-22 (IL-22) in mucosal host defense against Gram-negative bacterial pneumonia. IL-22, produced by T helper type 17 (T<H17) cells, was found to be crucial for maintaining local control of the pulmonary pathogen *Klebsiella pneumoniae*. Unlike IL-17A, IL-22 increased lung epithelial cell proliferation and transepithelial resistance to injury. In an experimental model of Gram-negative pneumonia, IL-22 was produced in a time-dependent manner and regulated by IL-23. Neutralizing IL-22 led to increased bacterial dissemination from the lung, exacerbated by the absence of IL-17A. IL-22 also increased the expression of host defense genes in mouse lung epithelium, with lipocalin-2 being essential for IL-22-induced epithelial antimicrobial activity. These findings support the concept that the T<H17 cell lineage and its effector molecules have evolved to mediate host defense against extracellular pathogens at mucosal sites.This study investigates the role of interleukin-22 (IL-22) in mucosal host defense against Gram-negative bacterial pneumonia. IL-22, produced by T helper type 17 (T<H17) cells, was found to be crucial for maintaining local control of the pulmonary pathogen *Klebsiella pneumoniae*. Unlike IL-17A, IL-22 increased lung epithelial cell proliferation and transepithelial resistance to injury. In an experimental model of Gram-negative pneumonia, IL-22 was produced in a time-dependent manner and regulated by IL-23. Neutralizing IL-22 led to increased bacterial dissemination from the lung, exacerbated by the absence of IL-17A. IL-22 also increased the expression of host defense genes in mouse lung epithelium, with lipocalin-2 being essential for IL-22-induced epithelial antimicrobial activity. These findings support the concept that the T<H17 cell lineage and its effector molecules have evolved to mediate host defense against extracellular pathogens at mucosal sites.