Cold-inducible RNA-binding protein (CIRP) was discovered 2 decades ago while studying the mechanism of cold stress adaptation in mammals. Since then, the role of intracellular CIRP (iCIRP) as a stress-response protein has been extensively studied. Recently, extracellular CIRP (eCIRP) was discovered to also have an important role, acting as a damage-associated molecular pattern, raising critical implications for the pathobiology of inflammatory diseases. During hemorrhagic shock and sepsis, inflammation triggers the translocation of CIRP from the nucleus to the cytosol and its release to the extracellular space. eCIRP then induces inflammatory responses in macrophages, neutrophils, lymphocytes, and dendritic cells. eCIRP also induces endoplasmic reticulum stress and pyroptosis in endothelial cells by activating the NF-B and inflammasome pathways, and necroptosis in macrophages via mitochondrial DNA damage. eCIRP works through the TLR4-MD2 receptors. Studies with CIRP −/− mice reveal protection against inflammation, implicating eCIRP to be a novel drug target. Anti-CIRP Ab or CIRP-derived small peptide may have effective therapeutic potentials in sepsis, acute lung injury, and organ ischemia/reperfusion injuries. The current review focuses on the pathobiology of eCIRP by emphasizing on signal transduction machineries, leading to discovering novel therapeutic interventions targeting eCIRP in various inflammatory diseases. K E Y W O R D S ALI, CIRP, DAMP, eCIRP, hemorrhage, inflammation, ischemia/reperfusion, macrophage, neutrophils, sepsis PMN, polymorphonuclear neutrophils; RA, rheumatoid arthritis; RM, reverse migrated; rTEM, reverse transendothelial migration; STAT3, signal transducer and activator of transcription 3; TRPV, transient receptor potential vanilloid; UC, ulcerative colitis telomerase maintenance, 7 stress adaptation, 8 and tumor formation and progression. 9,10 These iCIRP activities, which allow cells to cope with various cellular stress conditions, have been reviewed in detail. 8 In contrast to iCIRP, extracellular CIRP (eCIRP) was recently discovered to act as a damage-associated molecular pattern (DAMP) promoting inflammation and injury. 11 The identification of eCIRP as a new DAMP has originated a new era of investigation in inflammation pathobiology. Serum levels of eCIRP not only were found to be elevated in individuals admitted to the intensive care unit (ICU)with hemorrhagic shock (HS), but also correlated with organ injury. 11 Furthermore, it was demonstrated that eCIRP was able to promote inflammation independently. 11 In cells subjected to hypoxia, CIRP translocates from its usual location in the nucleus to the cytosol 1,12 and is then released to the extracellular space. 11 eCIRP then acts as a DAMP increasing macrophage production of proinflammatory cytokines. 11 Since its original discovery as a DAMP, eCIRP's emerging proinflammatory role has been progressively extended to include additional target cells, such as neutrophils, lymphocytes, epithelial cells, and endothelial cells. 13-2...