Systemic interleukin IL-1β, TNFα, and IL-2 profoundly influenced central monoamine activity, as well as behavioral outputs. The effects of the various cytokines were clearly distinguishable from one another, although synergistic effects were detected between several of these cytokines and between the actions of cytokines and stressors. Acutely applied IL-2 appeared to affect reward processes, but did not affect anxiety. When chronically administered, this cytokine markedly influenced working memory in a spatial learning test. In contrast to IL-2, both IL-1β and TNFα appeared to provoke an anxiogenic action, and provoked clear signs of illness. While these cytokines induced anorexia, they did not appear to affect reward processes. IL-1β and TNFα were found to act synergistically, and the TNFα provoked a sensitization with respect to the action of subsequent TNFα treatment. The findings indicated that cytokine treatments profoundly influence extrahypothalamic neurochemical functioning and may thus impact on behavioral outputs. Analyses of the behavioral and neurochemical changes elicited by cytokines, and particularly TNFα, need to consider not only the immediate impact of such treatments, but also the proactive effects that may be engendered.