The recent discovery of a new CD4⁺ T cell subset, Th17, has transformed our understanding of the pathogenetic basis of an increasing number of chronic immune-mediated diseases. Particularly in tissues that interface with the microbial environment—such as the intestinal and respiratory tracts and the skin—where most of the Th17 cells in the body reside, dysregulated immunity to self (or the extended self, the diverse microbiota that normally colonize these tissues) can result in chronic inflammatory disease. In this review, we focus on recent advances in the biology of the Th17 pathway and on genome-wide association studies that implicate this immune pathway in human disease involving these tissues.