The human gut is colonized by commensal bacteria that are essential for normal development and metabolism. In healthy individuals, these gut bugs inhabit the intestinal lumen, the epithelial surface and gut-associated lymphoid tissues, but in numerous chronic diseases, including Crohn's disease, they stray into surrounding tissues and cause inflammation. Inflammation is regulated by interleukin 22 (IL-22), which is produced by immune cells, including innate lymphoid cells (ILCs), a newly identified family of cells that seem to bridge the innate and adaptive immune systems in mammals. Sonnenberg et al. report that IL-22–producing ILCs are present in human, non-human primate and mouse intestinal samples. Antibody-mediated depletion of ILCs in mice resulted in bacteria (mainly Alcaligenes species) disseminating to the spleen and liver, with a concomitant increase in signs of inflammation. Case-control studies revealing Alcaligenes spp. in sera of pediatric Crohn's disease patients and cirrhotic hepatitis C virus-infected individuals confirm that loss of containment of gut bacteria is clinically relevant. Crucially, administering IL-22 in mice ameliorated the effects of ILC depletion and kept the gut bugs in their place. Taken together, these data support a model in which ILCs function to confine commensals to specific niches where they cannot cause harm and could pave the way to rational strategies to treat selected inflammatory diseases. (Science 336, 1321–1325, 2012)