During septic shock, cytokines produced by host cells play an important role in the pathogenesis of hemodynamic involvement and cellular lesions. Recently, natural inhibitory substances able to neutralize the biological activity of tumor necrosis factor alpha (TNF alpha) and interleukin-1 (IL-1) were described. These inhibitory molecules are involved in the regulation of the production of these cytokines. Thus, an understanding of these mechanisms could lead to new treatments for septic shock. A review of the interactions of TNF alpha with macrophages, neutrophils and endothelium underlines the key role of TNF alpha in 3 important events of septic shock: neutrophil adherence to endothelium, capillary leak syndrome, and development of disseminated intravascular coagulopathy. In clinical studies, circulating TNF alpha concentrations were elevated and correlated with the severity of the disease. Soluble TNF receptors (TNF-sRI and TNF-sRII) neutralize the biological effect of TNF alpha. Their circulating levels are also increased in meningococcemia, but an imbalance between TNF alpha and TNF-sR was found at the beginning of the disease which could determine the severity of the shock in these patients. The IL-1 system is composed of IL-1 alpha and IL-1 beta, two forms of precursors, two distinct receptors, two soluble fragments of the extramembranous regions of these receptors, and a natural antagonist of IL-1 receptors (IL-1 ra) which could be secreted or remain intracellular. IL-1 ra improved the outcome in some experimental diseases (endotoxemic shock, cerebral malaria arthritis, graft-versus-host reaction). The treatment of septic shock with IL-1 ra is currently being assessed in phase I and II clinical studies. Blockade of cytokines by antibodies or naturally occurring inhibitory molecules could lead to new therapies for septic shock.