Inflammation or inflammatory cytokines and oxidative stress have often been associated, and thiol antioxidants, particularly glutathione, have often been seen as possible anti-inflammatory mediators. However, whereas several cytokine inhibitors have been approved for drug use in chronic inflammatory diseases, this has not happened with antioxidant molecules. We outline the complexity of the role of protein thiol-disulfide oxidoreduction in the regulation of immunity and inflammation, the underlying molecular mechanisms (such as protein glutathionylation) and the key enzyme players such as Trx (thioredoxin) or Grx (glutaredoxin).