Interleukin 1, interferon alpha 2, and tumor necrosis factor alpha are cytokines that centrally mediate various reactions typical of the host defense responses to infection. The preoptic-anterior hypothalamus is an important, but not exclusive, integrative and controlling region for several of these effects. Although these cytokines display some common functional activities (e.g., pyrogenicity, somnogenicity), the characteristics of the responses they induce are different. Their effects, moreover, can be evoked or suppressed selectively, indicating that the neuronal substrates and/or neuromodulators used are distinct, each possessing discrete but partially overlapping sensory combinations. Nevertheless, it is not yet obvious how these systems are organized and integrated in host defense. It is also unclear whether these cytokines are elaborated peripherally and gain access to the brain or whether they are induced centrally. The available data suggest that circulating cytokines probably do not penetrate the brain but may activate elements in the organum vasculosum laminae terminalis. This site appears to be critically important for the production of the centrally mediated effects of blood-borne cytokines; it is speculated that the cytokines evoke there local signals that transduce their message; serotonin may be linked to these signals.