Tumor necrosis factor-alpha (TNF) exerts numerous influences which, in association with severe infection, subserve both detrimental as well as beneficial host responses. The current review addresses recent insights into the structure and function of this pleiotropic cytokine, with a particular emphasis upon cellular and organ system consequences of sepsis-induced TNF activity. A comparison of responses elicited by endotoxin or TNF administration are discussed as are mechanisms of endogenous TNF regulation, such as soluble receptors, anti-inflammatory cytokines, and counter-regulatory responses. A review of past and future clinical strategies for altering TNF activity during sepsis is also provided.