The effects of IL-17 antagonism in psoriasis at the molecular and cellular levels and the clinical responses in treated individuals therefore go far beyond the predictions of the mixed effect pathway model, suggesting a major revision to our thoughts about the interactions of different T cell subsets and cytokines in the pathogenesis of psoriasis and, perhaps, other inflammatory diseases. Further bench and translational studies are needed to better understand how IL-17 drives expression of hundreds to thousands of disease-related genes in the skin, as well as how IL-17 may interact with other cytokines to regulate genes in additive or synergistic modes. Pathogenic roles for IFN-γ and IL-22, if any, now need re-examination. Perhaps the role of TH1 cell immunity in psoriasis will be more similar to its role in experimental autoimmune encephalitis, in which IL-12 and TH1 cells may function to dampen the IL-23 and TH17 cell response11. The cellular source and regulation of IL-17 production in psoriasis also need better definition given that CD4+, CD8+ and γδ T cells are all potential sources, whereas mast cells and neutrophils have been suggested as alternative IL-17–producing cells. Severe psoriasis is associated with increased risk of cardiovascular disease. Additional scientific studies are needed to fully explore how IL-17, the concentration of which is highly elevated in the circulation of people with psoriasis compared to healthy subjects, may affect comorbid diseases that patients with psoriasis are at increased risk for. Notably, IL-17 seems to be emerging as a major risk cytokine for the development of cardiovascular diseases12, so IL-17 may have biological impact far beyond skin inflammation in psoriasis. Thus, bidirectional bedside-to-bench studies are now necessary to fully understand the role of IL-17 and its associated cellular producers in common inflammatory diseases of humans. The divergence of T cell subsets between mice and humans, as well as major differences in skin structure in humans compared to rodents (Fig. 1), argues for a need to deepen the understanding of cytokine mechanisms of skin inflammation in humans, where feasible. In addition, a major remaining question is whether psoriasis can be treated safely and effectively by long-term antagonism of just one cytokine: IL-17A.