The central nervous system regulates the innate immune system by elaborating anti-inflammatory hormone cascades in response to bacterial products and immune mediators. We recently discovered that the central nervous system also responds via acetylcholine-mediated efferent signals carried through the vagus nerve. Nicotinic cholinergic receptors expressed on macrophages detect these signals and respond with a dampened cytokine response. Vagus nerve stimulators can mimic this response and can prevent lethal endotoxemia. This newly appreciated cholinergic anti-inflammatory pathway provides a neural substrate to study brain-immune interactions and might be harnessed for therapy of cytokine-mediated disease.