The conceptual breakthrough that culminated with the realization that CD4+ T cells could differentiate from antigen-naïve precursors into distinct subsets of effectors with specialized immunoregulatory functions – the Th1–Th2 paradigm – rested on advances in cytokine biology, the development of methods for cloning T cells, and, ultimately, the introduction of transgenic mice with T-cell repertoires restricted to a single antigenic specificity. Over the past 20 years, the Th1–Th2 hypothesis has dominated the attention of CD4+ T-cell biologists and has provided a framework for understanding immune regulation and the interplay between innate and adaptive immune arms 1. In his historical perspective on Th1 and Th2 cells 7 years ago 2, Liew, current chairman of the Executive Committee of the European Journal of Immunology, detailed the series of discoveries leading up to the landmark paper by Mosmann and Coffman that characterized Th1 and Th2 subsets 3. He also recounted key discoveries that have provided an understanding of the signaling and transcriptional pathways controlled by reciprocal cytokine networks that lead to the differentiation of mature Th1 and Th2 cells. In the interval since that article was published, Th1 and Th2 have had to make way for a third effector lineage, Th17, the discovery of which, like its forebears, was propelled by identification of new cytokines: in this case, IL-23, a member of the IL-12 family, and IL-17, founding member of a novel cytokine family – and the new effector lineage's namesake (as reviewed in 4, 5). Although it was predicted in the original report describing Th1 and Th2 cells 3 that it was likely that other CD4+ T-cell subsets would be discovered, the relatively long period between conception of the Th1–Th2 hypothesis and the emergence of Th17 gives testament to the quality of the original Th1–Th2 model. Looking back with the advantage of hindsight, it is now clear that the original Th1–Th2 model was incomplete. Originally conceived as an explanation for two well-described patterns of immune-mediated inflammation (i.e. T-cell-mediated delayed-type hypersensitivity and IgE-mediated acute hypersensitivity or allergy), over time Th1 and Th2 cells came to be increasingly linked to innate and adaptive immune responses orchestrated in response to different types of pathogens. Specifically, Th1 immunity became linked to intracellular pathogens that can persist in phagocytic vesicles of macrophages, such as certain bacteria and protozoans, clearance of which is heightened by induction of opsonizing antibody isotypes (e.g. IgG2a in mice) and induction of heightened intracellular killing, both actions promoted by the Th1 signature cytokine, IFN-γ. In contrast, Th2 immunity was linked to host protection against complex parasites such as helminths, whose clearance is dependent on basophils and mast cells armed with IgE, and the recruitment and activation of eosinophils, through the coordinated actions of the cytokines IL-4, IL-13, and IL-5. Thus, the switching to IgE for the arming of basophils and mast cells (promoted by IL-4 and IL-13), the increased mucous production and motility of enteric and respiratory tracts (IL-13), and the increased production and recruitment of the eosinophils (IL-5) necessary for the optimal clearance of helminths are augmented by production of the indicated cytokines by Th2 cells. Accordingly, Th1 and Th2 appear to have evolved to coordinate B-cell antibody class-switching and innate immune cell recruitment/activation to most efficiently target specific classes of pathogens. Missing from this refined model of Th1 and Th2 immunity was a pathway for orchestrating clearance of extracellular bacteria and fungi, or recruitment of the remaining branch of innate immune effector cells, neutrophils, which are important for clearance of these pathogens. With the remarkably rapid emergence and characterization of the Th17 lineage, this gap has been filled and a more unified model of CD4 orchestration of monocytic (Th1), mast cell/basophilic/eosinophilic (Th2) and neutrophilic (Th17) patterns of inflammation by distinct CD4+ T-cell subsets is now apparent. A unified understanding of the inductive and effector cytokines particular to each effector subset has also emerged. Taking their place now alongside Th1 cytokines (IFN-γ and IL-12) and Th2 cytokines (IL-4, IL-5, and IL-13), are the Th17-associated cytokines, including the inductive cytokines IL-6, TGF-β, and IL-23, and the effector cytokines, IL-17A, IL-17F, and IL-22. With the addition of Th17, we now see a more complete evolutionary strategy for matching the host response to different types of pathogen. In effect, the “loop has been closed” with respect to CD4+ T-cell regulation of the innate cell and B-cell arms of immunity, such that each subclass of myeloid effector cell (monocyte/macrophage, basophil/mast cells/eosinophil, and neutrophil) now has its dedicated T-cell effector pathway that is coupled to the antibody isotypes that enhance functions of each. As with Th1 and Th2, the evolutionary pressures to produce a T-cell pathway tailored for protection against those pathogens targeted by Th17 came with implicit risk. The dark side of any immune response is self-destructive immunity. In the case of Th17, the risk to self appears to be particularly high. Indeed, it was appreciation of the fact that the IL-17–IL-23 inflammatory axis was responsible for several key models of autoimmune disease originally attributed to dysregulated Th1 immunity that eventually led to the discovery of Th17 (reviewed in 6). More recently, a growing list of human chronic inflammatory diseases has been linked to Th17 through genetic association studies and identification of Th17-specific biomarkers, such that Th17 has seized center stage in a number of major autoinflammatory disorders, including rheumatoid arthritis, inflammatory bowel disease, and psoriasis, among others – each originally thought to be a Th1-mediated disease. Given the relatively brief period since Th17 was identified as an effector arm distinct from Th1 and Th2 7, 8, the detail with which this pathway is now understood is nothing short of remarkable. This fast start for Th17 is owed in large part to the wealth of knowledge accumulated in studies of Th1 and Th2 lineage development and function that preceded discovery of Th17, providing a technical and conceptual framework for rapid delineation of the Th17 pathway. Collected in this Viewpoints series are articles that reflect the breadth and depth of our current understanding of the Th17 pathway by a number of the leading contributors to the Th17 field. Soon after its description as a distinct developmental lineage 7, 8, Th17 was linked to the development of induced Treg (iTreg) by virtue of the shared inductive cytokine, TGF-β 9-12. In his Viewpoint article, Dong reprises studies leading to the appreciation of the Th17 as an independent lineage and discusses links to the iTreg pathway and the signaling and transcription factors that distinguish Th17 and iTreg differentiation 13. He also speculates on the relationship between Th17 and follicular helper cells. Stockinger et al. describe their recent shared discovery of a ligand-activated transcription factor, the aryl hydrocarbon receptor, and speculate on its role in modulating Th17 development via a range of endogenous and environmental ligands 14. Weiner, whose group co-discovered aryl hydrocarbon receptor expression by Th17 cells, offers a complementary review (co-authored by Quintana) of this factor's role in T-cell development and integrates these findings with recent discoveries that have identified roles for vitamin A metabolites and products of the commensal bacterial flora in modulating Th17-cell responses at mucosal sites 15. In an article that considers key cytokines involved in the development and function of the Th17 pathway, Spolski and Leonard explore possible subset diversity within the broader Th17 developmental pathway based on heterogeneity in cytokine secretion patterns at the level of single cells 16. O'Brien et al. discuss the importance of γδ T cells that have recently come to the fore as a prominent IL-17-producing subset, and which may bridge innate and adaptive responses provoked by certain pathogens 17. Considering the specific roles of Th17 in host defense, the articles by Cooper and Romani and co-workers discuss the respective roles for IL-17 cytokines and the Th17 pathway in anti-bacterial 18 and anti-fungal immunity 19, respectively. An area of considerable controversy at present concerns possible points of difference between Th17 developmental pathways in mouse and man. Romagnani and co-workers, who were instrumental in resolving early controversies regarding possible differences in murine and human Th1 and Th2 cells, explore the current state-of-the-art regarding similarities and differences between murine and human Th17 lineages 20. This piece sets the stage for discussions by Miossec 21 and Ouyang et al. 22, who address clinical implications of the Th17 pathway and define targets for therapeutic intervention in human diseases linked to Th17. As should be evident from the views expressed in this collection of articles, the impact of Th17 pathway on our understanding of the basic mechanisms of immune regulation and Th17's potential to profoundly alter our understanding of immune pathogenesis of a growing number of human inflammatory diseases offer considerable hope for new strategies for control of these disorders. However, these articles also point out areas of contention and highlight the divergence of opinions that naturally arise from scientific inquiry in an area that has developed with such rapidity and intensity. Aside from the excitement generated by the very tangible promise that Th17 holds for novel interventions for autoimmunity, transplantation, and vaccine design, perhaps equally compelling is the fresh perspective that the discovery of Th17 has provided on its more established forebears. Th1 and Th2 have lost none of their luster for sharing the stage with an upstart sibling new to the act. In many ways, Th17 has reinvigorated interest in Th1 and Th2 and, perhaps, provided a bit of relief for the older siblings such that they can now go about their business with a bit less fanfare as the new kid on the block garners much of the limelight – for now at least. The author thanks members of his lab for helpful discussions and Gloria Gaskins for editorial assistance. The author's lab is supported by grants from NIAID, NIAMS, and NIDDK of the National Institutes of Health, the Crohn's and Colitis Foundation of America (CCFA) and Daiichi-Sankyo Co., Ltd. Conflict of interest: The author declares no financial or commercial conflict of interest. See accompanying articles: all the Viewpoint articles in this series Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.