Following its cloning through an homology-based method from a rat striatal library, the calcium-sensing receptor (CaR) has been localized in the brains of adult and developing rats by immunocytochemistry and in situ hybridization with CaR-specific antibodies and cDNA probes, respectively. The receptor resides in numerous regions of the brain at widely varying levels. The highest levels are present within the subfornical organ (SFO) and the olfactory bulbs. Substantial levels of expression are also evident within the hippocampus, striatum, cingulate cortex, cerebellum, ependymal zones of the cerebral ventricles, and perivascular nerves around cerebral arteries. There are abundant levels of CaR expression within the SFO, an important hypothalamic thirst center, suggesting that it participates in the central control of systemic fluid and electrolyte balance. Therefore, while mineral ion homeostasis is not often considered to have central regulatory elements (i.e. in the brain), there are perhaps more complex relationships than recognized previously among the system governing mineral ion homeostasis and other homeostatic systems known to exhibit prominent neuroendocrine elements (i.e. water homeostasis). Furthermore, the expression of the CaR in all three types of glial cells indicates potential roles in the maintenance of local ionic homeostasis as well as in disease processes such as glioma.