Neuro-inflammation is a common feature of various central nervous system (CNS) disorders, including stroke, Alzheimer's disease, Multiple sclerosis, etc., and has a significant impact on the outcomes. Regulation of the immune response has therapeutic value. Interferon regulatory factor 4 (IRF4) is a hemopoietic transcription factor critical for activation of microglia/macrophages and modulation of inflammatory responses. The effects of IRF4 signaling on inflammation are pleiotropic, and vary depending on immune cell types and the pathological microenvironment that is regulated by both pro- and anti-inflammatory cytokines. Mechanistically, IRF4 is a quintessential 'context-dependent' transcription factor that regulates distinct groups of inflammatory mediators in a differential manner depending on their activation in different cell types including phagocytes, T-cell subtypes, and neuronal cells. In this review, we summarized the recent findings of IRF4 in the context of immune responses in different cell types with diverse pathological conditions. The primary goal of this review is to understand the signaling pathways and beneficial functions of IRF4, in hope of developing effective therapeutic strategies targeting the immune responses to neurodegenerative diseases.