The composition of cerebrospinal and brain interstitial fluids is ensured by barriers between the blood and the brain parenchyma (the blood-brain barrier) and between the blood and the cerebrospinal fluid (the blood-cerebrospinal fluid barrier). Barrier function results from the combination of tight junctions between cells that impair solute flux via the paracellular pathway, cell membrane transporters that enable selective transcellular solute passage, and intracellular metabolizing enzymes that transform molecules in transit. Collectively, they comprise a chemical surveillance system, essential to protect the brain from toxicants, microorganisms, and other harmful compounds. Conversely, this chemical surveillance system compromises the brain delivery of many pharmacologic agents against brain cancer and brain metastasis, neurodegenerative diseases, and brain infections. Despite their importance, the mechanisms underlying the regulation of the components of this chemical surveillance system in response to alterations in the composition of blood and brain fluids are still poorly understood. We propose that odorant receptors, vomeronasal receptors and taste receptors, recently identified at brain barriers might be upstream components of this surveillance system. These chemosensory receptors are strategically placed to monitor the composition of blood, cerebrospinal and brain interstitial fluids. Upon ligand-binding, they may deploy the action of transporters and detoxifying enzymes or other unprecedented functions in brain barrier cells, to cope with alterations in the composition of blood and brain cerebrospinal and interstitial fluids, working as guardians of the central nervous system.