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Interferon (IFN) regulatory factors (IRFs) are transcription factors with versatile functions in the regulation of innate and adaptive immune responses. In the current issue of the European Journal of Immunology, Steinhagen et al. [Eur. J. Immunol. 2013. 43: 1896–1906] investigate the regulation of IFN‐β and IL‐6 induction in human plasmacytoid DCs stimulated with CpG DNA. Using RNA interference studies, the authors identify critical roles for IRF5 and IRF8 as positive and negative regulators, respectively. In contrast, knockdown of IRF7 had no significant effect on IFN‐β or IL‐6 gene induction. In this Commentary, these findings are discussed in the context of the published literature and recent data regarding IRF5 and IRF8 as susceptibility genes for autoimmunity.