Abstract. Proinflammatory mediators such as tumor necrosis factor-alpha (TNF) have been implicated in the pathophysiology in a number of acute disease states. Tumor necrosis factor-alpha can contribute to cell death, apoptosis, and organ dysfunction. Tumor necrosis factor-alpha can be generated with sepsis or ischemia-reperfusion by activation of cell mitogen-activated protein kinases and nuclear factor kappa B, leading to TNF production. A number of strategies to modulate TNF have been recently explored, including factors directed toward mitogen-activated protein kinases, TNF transcription, anti-inflammatory ligands, heat shock proteins, and TNF-binding proteins. However, TNF may also play an important role in the adaptive response to injury and inflammation. Control of the deleterious effects of TNF and other proinflamatory cytokines represents a realistic goal for clinical emergency medicine. The purpose of this article is to provide a background of relevance to emergency medicine academicians on the production and regulation of TNF, the acute effects of TNF on pathophysiology, and the rationale for therapeutic interventions directed toward TNF and the clinical experience with these strategies. Key words: sepsis; shock; ischemia and reperfusion; therapy; trauma; emergency; review; tumor necrosis factor. ACA-DEMIC EMERGENCY MEDICINE 2000; 7:930-941 I NFLAMMATORY cytokines are known to be important mediators of numerous disease states faced by emergency physicians.1-8 A basic understanding of inflammatory cytokines and their relationship to acute disease is of growing importance to laboratory scientists, clinical researchers, and clinicians. Tumor necrosis factor-alpha (TNF) is a proinflammatory cytokine that has been directly implicated in the pathogenesis of many acute disease states, including sepsis, traumatic injury, cardiac and cerebral ischemia, asthma, and burns. [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16] Tumor necrosis factor-alpha may also play an important role in the adaptive response to injury and inflammation. 14 The intracellular signal pathways that provoke TNF production have been the subject of intense investigations. 10,17,18 In particular, the discovery of Other therapeutic targets include the activation of endogenous anti-inflammatory strategies such as ligands for the gp130 subunit, the induction of heat shock proteins (HSPs), and infusion of TNF-binding proteins. These approaches hold the promise of directly modulating the destructive role of proinflammatory cytokines, such as TNF, in acute disease states.The purpose of this article is to provide a background of relevance to emergency medicine academicians on the production and regulation of TNF, the acute effects of TNF on pathophysiology, and the rationale for therapeutic interventions directed toward TNF and the clinical experience with these strategies.