In the central nervous system, the Na(+)/Ca(2+) exchanger plays a fundamental role in controlling changes in the intracellular concentrations of Na(+) and Ca(2+) ions that occur in physiologic conditions such as neurotransmitter release, cell migration and differentiation, gene expression, as well as neuro-degenerative processes. Three genes, NCX1, NCX2, and NCX3, encoding for Na(+)/Ca(2+) exchanger isoforms have been cloned. In this review, by using non-radioactive in situ hybridization and light immunohistochemistry with NCX isoform-specific riboprobes and antibodies, respectively, a systematic brain mapping for both transcripts and proteins encoded by all three NCX genes is described. Intense expression of NCX transcripts and proteins was detected in the cerebral cortex, hippocampus, thalamus, metathalamus, hypothalamus, brainstem, spinal cord, and cerebellum. In these areas, NCX transcripts and proteins were often found with an overlapping distribution pattern, although specific brain areas displaying a peculiar expression of each exchanger isoform were also found. Furthermore, immunoelectron and confocal microscopy revealed the expression of the NCX1 isoform of the exchanger at both pre- and postsynaptic sites as well as in association with membranes of the endoplasmic reticulum. Collectively, these data suggest that the different isoforms of the Na(+)/Ca(2+) exchanger appear to be selectively expressed in several CNS regions where they might underlie different functional roles.