Neurons do not have receptors to detect bacteria or viruses, yet the presence of these microorganisms can cause a sickness behavior syndrome that includes, e.g., fever, anorexia, and lethargy. Because the immune system has receptors capable of detecting these non-cognitive stimuli, how the immune system transmits a message to the brain has been studied to understand why behavior is altered in sick animals. The focus has been on several cytokines secreted by leukocytes; these include interleukin (IL)-1beta, IL-6, and tumor necrosis factor-alpha (TNF-alpha). These cytokines are secreted by activated mononuclear phagocytic cells, and numerous studies show that both peripheral and central injection of IL-1beta, IL-6, and TNF-alpha induce sickness behavior. Moreover, these cytokines and their receptors are present in the brain and inhibiting the secretion of cytokines or blocking their receptors in the brain blocks or abrogate the behavioral responses induced by inflammatory stimuli. Because the sickness behavior syndrome modulates the immune system and enhances recovery, the interplay between the immune system and central nervous system is an essential part of the overall host defense against pathogenic microorganisms. The purpose of this brief paper is to provide a chronological description of four critical advances that have led to the current understanding of how the immune system communicates with the brain to induce sickness behavior. Results from several key studies will be discussed, which showed that: (1) sickness behavior is a motivational state; (2) sickness behavior is a well-organized adaptive response to infection; (3) cytokines produced by activated leukocytes induce sickness behavior; and (4) cytokines transmit messages from the periphery to the brain using humoral and neural pathways.