Circulating inflammatory mediators can signal neurons through a pathway in which cytokine activation of the cells of the blood–brain barrier causes the induction of the nuclear factor kappa B (NF-κB), leading to the transcription of target genes, such as the one encoding cyclooxygenase 2 (COX-2), the enzyme that initiates prostaglandin formation. These active products of the arachidonate metabolism produced by the cerebral microvasculature have critical roles in initiating the neuronal responses and the neurophysiological outcomes that take place during immunogenic stimuli, including sickness behaviors, fever and increase in the hypothalamic-pituitary adrenal axis. Whether there is more than a single cell type in the blood–brain barrier responsible for the synthesis of prostanoids in the presence of circulating proinflammatory cytokines is an interesting debate that will be summarized here.