Ubiquitin is a post-translational protein modifier and plays essential roles in all aspects of biology. Although the discovery of ubiquitin introduced this highly conserved protein as a molecule with extracellular actions, the identification of ubiquitin as the ATP-dependent proteolysis factor 1 has focused subsequent research on its important intracellular functions. Little attention has since been paid to its role outside of the cell. During recent years, multiple observations suggest that extracellular ubiquitin can modulate immune responses and that exogenous ubiquitin has therapeutic potential to attenuate exuberant inflammation and organ injury. These observations have not been integrated into a comprehensive assessment of its possible role as an endogenous immune modulator. This review recapitulates the current knowledge about extracellular ubiquitin and discusses an emerging facet of its role in biology during infectious and noninfectious inflammation. The synopsis of these data along with the recent identification of ubiquitin as a CXCR4 agonist suggest that extracellular ubiquitin may have pleiotropic roles in the immune system and functions as an endogenous opponent of DAMPs. Functions of extracellular ubiquitin could constitute an evolutionary conserved control mechanism aimed to balance the immune response and prevent exuberant inflammation. Further characterization of its mechanism of action and cellular signaling pathways is expected to provide novel insights into the regulation of the innate immune response and opportunities for therapeutic interventions.