The mononuclear phagocyte system regulates tissue homeostasis as well as all phases of tissue injury and repair. To do so changing tissue environments alter the phenotype of tissue macrophages to assure their support for sustaining and amplifying their respective surrounding environment. Interferon-regulatory factors are intracellular signaling elements that determine the maturation and gene transcription of leukocytes. Here we discuss how several among the 9 interferon-regulatory factors contribute to macrophage polarization.