Cytokines released from activated immune cells can act on the brain to elicit a range of centrally mediated acute phase responses. Several lines of evidence point to the barriers between the brain and its fluid environments, mainly cells associated with the cerebral vasculature, as critical sites for the transduction of circulating cytokine signals, and the initiation of brain responses to them by virtue of their capacity to produce local signaling molecules, notably prostaglandins. While it was initially assumed that such functions were the province of the vascular endothelium, recent work has identified a subset of marrow-derived brain macrophages, termed perivascular cells, as exhibiting the greater sensitivity to prostanoid synthesis induced by systemic cytokine or endotoxin challenges. Application of a novel liposome-based targeting method supports a critical involvement of brain macrophages, and their capacity to manifest induced prostanoid synthesis, in the interleukin-1-induced recruitment of control circuitry governing at least one acute phase response (hypothalamo-pituitary-adrenal axis activation), and suggests a two-way interaction between perivascular and endothelial cells in monitoring circulating cytokine signals. The ability to selectively manipulate perivascular cells holds promise for further informing mechanisms of immune-to-brain, and for intervening in pathologies that may result from dysfunction of such interactions.