Interferon regulatory factor 5 (IRF5) has described as an important factor in regulating inflammatory response and a key transcription factor in the immune system. In antiviral response, IRF5 promote the expression of type 1 interferon (IFN) and also is important in the differentiation of macrophage towards pro-inflammatory phenotype, regulating B Cell maturity and antibody production. Some of the cancerous patients treated by IFNα manifest symptoms resembling systemic lupus erythematosus (SLE). One of the important mechanism in this response is IRF5 that trigger apoptosis. Herein, we discuss around functional importance of IRF5 in rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) in a setting of polymorphic mutations at the human Irf5 locus. We also describe the mice models and the lessons of IRF functionality in these models and the consequence of autoimmune diseases. In conclusion, we hypothesize that modulation of IRF5 activity could be beneficial in autoimmune diseases therapies.