The psychologic and behavioral components of sickness represent, together with fever response and associated neuroendocrine changes, a highly organized strategy of the organism to fight infection. This strategy, referred to as sickness behavior, is triggered by the proinflammatory cytokines produced by activated cells of the innate immune system in contact with specific pathogen-associated molecular patterns (PAMPs). Interleukin-1 and other cytokines act on the brain via (1) a neural route represented by the primary afferent neurons that innervate the body site where the infectious process takes place and (2) a humoral pathway that involves the production of proinflammatory cytokines. This article presents the current knowledge on the way this communication system is organized and regulated and the implications of these advances for understanding brain physiology and pathology.