Immune and central nervous system (CNS) interactions are complicated because afferent signals from the immune system to the CNS in response to antigens or infections may elicit an immediate efferent response to the immune system. This communication loop is required for the homeostatic regulation of the immune system. Conditioning can be used as a tool to take the communication loop apart. In conditioned animals, the conditioned stimulus can be employed later to trigger the site of the association memory located within CNS, and set off the efferent pathway. Conditioning therefore allows one to isolate and identify the potential circuits in the brain that becomes conditioned. We have conditioned a pathway in the brain which can be used to modulate core body temperature (Tc) and natural killer (NK) cell activity. The Tc and NK cell activity are used as readouts to detect the expression of the conditioned response which is taking place in the brain. Since various cytokines (IFN, IL-1 etc.) that are produced by antigenic stimulation invariably raise fever, it appears that the immune system could signal the CNS with nonspecific cytokines that activate the hypothalamic-pituitary pathway to modulate core body temperature. These observations infer that the thermoregulatory pathway in the brain becomes conditioned and points to a common pathway of communication in which interferon-β, prostaglandin E2, CRH and ACTH appear to play a role in modulating both Tc and NK cell activity.