Interferon regulatory factors (IRFs) were first identified during studies of type I interferons. Since then, many investigations have established that IRFs are involved in regulating the innate immune response, the development of various immune cell types, and carcinogenesis. Several genetic studies have identified genetic variants, most notably IRF5, associated with an increased risk of autoimmune disease. The biological role for IRFs in autoimmune diseases has been evaluated not only in vitro, but also in vivo in various murine models. Here, we discuss the role for the various IRFs, particularly in toll-like receptor signaling pathways. We also review the evidence supporting a role for IRFs in dysimmune diseases.