The anti-viral proteins, interferons (IFNs), are central to the immune response during viral infection. The major regulators of interferons are the interferon regulatory factors (IRFs) which transcriptionally regulate IFN expression and command the IFN system as a whole.  There are nine members of the mammalian IRF family (IRF1-9). Studies of mouse IRF-knockout models for these nine members indicate that IRFs actually possess a variety of functional roles, some of which are not directly associated with the IFN system [reviewed in (1)]. IRFs regulate hematopoiesis as well as the growth and development of other non-blood cell types. IRF4 and IRF8 are critical to B-cell and dendritic cell development, while IRF6 has been found to be a key regulator of keratinocyte development. Although most IRFs play major roles in the induction of type I IFNs, IRF3 and IRF7 have been found to be especially important [reviewed in (1) and  (2)]. IRFs themselves are highly regulated via post-transcriptional modifications such as acetylation, phosphorylation, sumoylation, and ubiquitination. Additionally, their localization, interactions with other nuclear factors, as well as their interactions in the chromatin environment are notably dynamic indicating a further complexity of their commanding roles [reviewed in (2)]. Because of this dynamic complexity, a systems-level approach to studying the regulatory transcriptional networks of the IRF family and the IFN system will provide a better understanding of their diverse roles in the development of both the innate and adaptive immune responses.