It is becoming well accepted that products of the immune system (cytokines) can signal the brain that infection has occurred. This cytokine-to-brain communication can result in marked alterations in brain function and behavior. This review examines alternative mechanisms that have been proposed to explain how such immune products can reach the brain via the blood to cause centrally-mediated "illness" responses. Finally, we describe a new view which argues that cytokines signal brain in quite a different manner, by stimulating afferent terminals of peripheral nerves at local sites of synthesis and release.