Interferon regulatory factor 5 (IRF5) is a crucial transcription factor in a number of immune and homeostatic processes, including host defense against pathogens, tumorigenesis, and autoimmunity. Upon induction of immune signaling pathways, IRF5 undergoes post-translational modifications such as phosphorylation and ubiqutination, which are believed to trigger IRF5 nuclear translocation from the cytosol, followed by recruitment to promoters where transcription of its gene targets is initiated. In this review, we systematically analyze the data published in the last decade on IRF5 activation, including the role of post-translational modifications and the proposed enzymes targeting IRF5 in this process. We discuss suggested models of IRF5 activation in connection to pathway-specific functions of IRF5.