Recent evidence has demonstrated that specific inhibitors of the proinfiammatory cytokines, IL-1 and TNFα, circulate in the blood of healthy individuals and concentrations of these inhibitors are elevated in inflammation. Initial characterization reveals that one of the classes of IL-1 inhibitors that circulates is the newly described IL-1 receptor antagonist (IL-lra). A class of newly described TNF inhibitors is the soluble type I (p55) and type II (p75) TNF receptor (sTNFR). In patients with nonlethal infections, both IL-lra and sTNFR appear to circulate at levels that can block the quantities of IL-1 and TNFα produced. However, such concentrations of inhibitors are inadequate to prevent the deleterious host responses to exaggerated proinfiammatory concentrations seen in lethal septic shock. Nevertheless, administering either IL-lra or soluble TNF receptors to raise plasma concentrations 1,000-fold can prevent the pathologic sequelae associated with excessive cytokine production.