Na(+)/H(+) exchangers (NHEs) conduct the electroneutral exchange of proton (H(+)) and sodium (Na(+)) ions across cellular membranes down their concentration gradients. To date, nine NHE family members have been cloned from mammals and share a common secondary structure. The ubiquitous exclusive plasma membrane NHE isoform 1 (NHE1) is a major membrane transport mechanism in regulation of intracellular pH (pH(i)) and volume. In addition to its role in regulation of ionic homeostasis, NHE1 can directly interact with other regulatory cellular signaling pathways, including modulation of the activity of mitogen-activated protein kinases (MAPKs) and Akt/protein kinase B (PKB). Thus, NHE1 is a multifaceted regulator of cell migration, proliferation, and cell death. NHE1 also plays pivotal roles under a number of pathophysiological conditions such as osmotic stress, acidosis, and mechanical stress. NHE1 is the most abundant NHE isoform in the rat central nervous system (CNS). This review discusses distribution and regulation of NHE1, and its physiological roles in the CNS. Moreover, it includes an extensive presentation of studies on activation of NHE1 under ischemic conditions in the CNS and its impact on Na(+) and Ca(2+) ionic homeostasis as well as on cell survival and damage.