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Abstract. There are exciting new developments regarding the molecular mechanisms involved in the influence of circulating proinflammatory molecules within cells of the blood-brain barrier (BBB) during systemic immune challenges. These molecules, when present in the circulation, have the ability to trigger a series of events in cascade, leading to either the mitogen-activated protein (MAP) kinases/nuclear factor kappa B (NF-κB) or the janus kinase (JAK)/signal transducer and activator of transcription (STAT) transduction pathways in vascular-associated cells of the central nervous system (CNS). The brain blood vessels exhibit both constitutive and induced expression of receptors for different proinflammatory ligands that have the ability to stimulate these signaling molecules. Depending on the challenges and the cytokines involved, the transduction signal(s) solicited in cells of the BBB may orient the neuronal activity in a very specific manner in activating the transcription and production of soluble factors, such as prostaglandins (PGs). It is interesting to note that cytokines as well as systemic localized inflammation stimulate the cells of the BBB in a nonselective manner (i.e., within both large blood vessels and small capillaries across the brain). This nonselectivity raises several questions with regard to the localized neuronal activation induced by different experimental models of inflammation and cytokines. It is possible that the selectivity of the neuronal response is a consequence of the fine interaction between nonparenchymal synthesis of soluble mediators and expression of specific receptors for these ligands within parenchymal elements of different brain nuclei. This review will present the recent developments on this concept and the mechanisms that take place in cells of the BBB, which lead to the neuronal circuits involved in restoring the body's homeostasis during systemic immunogenic challenges. The induction of fever, the hypothalamic-pituitary adrenal (HPA) axis, and other autonomic functions are among the physiological outcomes necessary for the protection of the mammalian organism in the presence of foreign material.