Interferon regulatory factor 5 (IRF5) has been described as an important factor in regulating inflammatory response and a key transcription factor in the immune system. In antiviral response, IRF5 promotes the expression of type 1 interferon (IFN) and is also important in the differentiation of macrophages towards pro-inflammatory phenotypes, regulating B-cell maturity and antibody production. Some cancer patients treated with IFNα manifest symptoms resembling systemic lupus erythematosus (SLE). An important mechanism in this response is IRF5 that triggers apoptosis. Herein, we discuss the functional importance of IRF5 in rheumatoid arthritis (RA) and SLE in a setting of polymorphic mutations at the human Irf5 locus. This paper describes murine models, the lessons of IRF functionality learned from these models and the consequences of autoimmune diseases. It is hypothesized that modulation of IRF5 activity may be beneficial in autoimmune diseases therapies.