Immune responses are initiated and perpetuated by molecules derived from microorganisms pathogen-associated molecular-pattern molecules or from the damage or death of host cells [damage-associated molecular-pattern (DAMP) molecules]. Many DAMPs are nuclear or cytosolic proteins with defined intracellular function that, when released outside the cell following tissue injury, move from a reducing to an oxidizing milieu resulting in their functional denaturation. Here, we discuss the consequences of DAMP oxidation on the outcome of acute inflammation. We also suggest that, outside the cell, DAMPs might adopt novel conformations or alter the redox of the extracellular environment to more closely mimic the internal one, thereby avoiding oxidation-mediated inactivation and promoting pathology. We propose that chronic inflammation associated with autoimmunity, chronic viral infection and cancer is probably mediated by persistent release and function of DAMPs, promoting and promoted by a disordered redox environment.