The prognostic implications of declining plasma gelsolin levels have been documented after a diverse variety of acute insults. Because gelsolin concentrations fall prior to the development of complications, a pathophysiological role for gelsolin depletion has been postulated in delayed multiorgan failure. The original hypothesis about the function of circulating gelsolin was that it scavenged actin released from cells at the site of injury. Although extracellular actin may be the primary cause of gelsolin depletion, the biologic imperative for gelsolin could entail the modulation of several inflammatory mediators as much as the disposal of actin. Translational research is actively addressing whether replenishment of plasma gelsolin could provide an efficacious and well tolerated therapeutic intervention in selected seriously ill patients.