Recent findings indicate that the role of Th17 cells in the pathogenesis of tissue inflammation and autoimmunity has become rather complicated. While interleukin-17 (IL-17) producing CD4+ T cells are found frequently within the peripheral target tissue during the course of autoimmune disease, these cells may contribute to or protect from inflammation. Accumulating reports have revealed the existence of both pathogenic and non-pathogenic Th17 cells. These Th17 subsets produce the signature cytokines IL-17A and IL-17F yet have distinct and divergent roles in inducing autoimmune tissue inflammation. Comparative genomic sequence analyses between the pathogenic and non-pathogenic Th17 cells have exposed unexpected and extensive population heterogeneity within the Th17 subset. Here we review some of the unexpected factors that may drive pathogenic divergence. Understanding the functional consequences of Th17 cell diversity may allow for the selection of more precise targets for intervention in autoimmune and inflammatory diseases.