Plasma fibronectin may be an important component of host defense in critically ill patients, particularly after trauma and during sepsis. This paper reviews recent studies that have sought to characterize the natural history of plasma fibronectin during sepsis, as well as those studies that tested the effect of therapy with concentrated fibronectin in sepsis. The decrease in plasma fibronectin that generally is seen in humans during sepsis probably is due to many factors, and it has been difficult to produce a similar pattern in animal models. Depletion of plasma fibronectin is not a sensitive or specific predictor of imminent sepsis, and once sepsis is established, the concentration of plasma fibronectin is no more sensitive a predictor of mortality than are many other clinical markers. Early, uncontrolled trials of therapy with a fibronectin concentrate in patients with sepsis appeared to indicate a propitious effect on organ function. However, more recent controlled trials have failed to show a significant effect of therapy with fibronectin concentrate on either organ function or patient survival.