This review discusses the role of IRF3 in sepsis and the current gaps in sepsis immunology. Sepsis is a life-threatening condition caused by the body's response to infection, leading to systemic inflammation and organ failure. Lipopolysaccharide (LPS) from gram-negative bacteria activates Toll-like receptor 4 (TLR4), triggering immune responses that can lead to septic shock. TLR4 signaling can proceed through two pathways: the MyD88-dependent pathway, which leads to the production of inflammatory cytokines, and the TRIF-dependent pathway, which activates interferon (IFN) production. IRF3 is a key transcription factor involved in the production of IFN-β and other antiviral genes. IRF3 is activated by various signaling pathways, including TLR4/MD-2, RIG-I, MDA5, and STING. IRF3 deficiency reduces IFN-β production and increases survival in sepsis models. However, IRF3 activation can also exacerbate sepsis by promoting inflammation and tissue damage. Recent studies have shown that IRF3 is involved in pathogen clearance and gut microbiota modulation. Inhibitors of IRF3, such as piceatannol and fucoxanthin, have shown potential in reducing sepsis severity. Despite these advances, there are still significant gaps in understanding the immune mechanisms underlying sepsis, including the role of epigenetic regulation, the gut microbiota, and the interplay between different immune pathways. Addressing these gaps is crucial for developing more effective treatments for sepsis.This review discusses the role of IRF3 in sepsis and the current gaps in sepsis immunology. Sepsis is a life-threatening condition caused by the body's response to infection, leading to systemic inflammation and organ failure. Lipopolysaccharide (LPS) from gram-negative bacteria activates Toll-like receptor 4 (TLR4), triggering immune responses that can lead to septic shock. TLR4 signaling can proceed through two pathways: the MyD88-dependent pathway, which leads to the production of inflammatory cytokines, and the TRIF-dependent pathway, which activates interferon (IFN) production. IRF3 is a key transcription factor involved in the production of IFN-β and other antiviral genes. IRF3 is activated by various signaling pathways, including TLR4/MD-2, RIG-I, MDA5, and STING. IRF3 deficiency reduces IFN-β production and increases survival in sepsis models. However, IRF3 activation can also exacerbate sepsis by promoting inflammation and tissue damage. Recent studies have shown that IRF3 is involved in pathogen clearance and gut microbiota modulation. Inhibitors of IRF3, such as piceatannol and fucoxanthin, have shown potential in reducing sepsis severity. Despite these advances, there are still significant gaps in understanding the immune mechanisms underlying sepsis, including the role of epigenetic regulation, the gut microbiota, and the interplay between different immune pathways. Addressing these gaps is crucial for developing more effective treatments for sepsis.