Introduction DURING the past few years, a variety of cytokines have been isolated and synthesized in abundance by molecular cloning techniques. One of these, a molecule known as “cachectin” or “tumor necrosis factor,” has emerged as an important component of the inflammatory response. Cachectin is produced by extravascular effector cells (principally macrophages) in response to invasive stimuli, and circulates throughout the body. Cachectin activates neutrophils, alters the properties of vascular endothelial cells, and regulates the metabolic activities of a variety of other tissues as well. Through its multiple effects, cachectin mediates many of the effects of endotoxin, both untoward and beneficial. Moreover, it induces a state of anorexia and wasting similar to that observed in chronic neoplastic and infectious diseases. Thus, this single protein mediator may play a central role in the pathogenesis of diverse disease states. Cachectin, an important factor in numerous physiological processes, was independently isolated by workers concerned with very different biological phenomena. As “cachectin,” it was isolated as a result of inquiry into the mechanism of wasting in chronic disease; as “tumor necrosis factor,” it was isolated as a result of inquiry into the cause of tumor necrosis occurring in the setting of infection. These two lines of investigation, and the molecule that they disclosed, are reviewed here.