The innate immune system is activated by infection and injury to release pro-inflammatory cytokines, which activate macrophages and neutrophils and modulate specific cellular responses. The magnitude of the cytokine response is critical, because a deficient response may result in secondary infections, while an excessive response may be more injurious than the original insult. We recently described a neural pathway, termed the "cholinergic anti-inflammatory pathway", that reflexively monitors and adjusts the inflammatory response by inhibiting pro-inflammatory cytokine synthesis. Efferent signals in the vagus nerve provide a direct mechanism for neural regulation of the immune response that is rapid, localized, and integrated. Vagus nerve stimulation inhibits the release of TNF, HMGB1, and other cytokines, and protects against endotoxemia and ischemia-reperfusion injury. This newly identified physiological mechanism of maintaining immunological homeostasis suggests that novel therapeutics may effectively modulate inflammatory responses by activating the cholinergic anti-inflammatory pathway.