The Na(+)/Ca(2+) exchanger (NCX) participates in the regulation of neuronal Ca(2+) homeostasis and is also believed to be involved in the neuronal responses to hypoxia. However, there are very limited data on how NCX mRNA and protein expression are regulated during brain development. In the present study, we sought to elucidate the developmental expression of NCX1 and NCX2 in the rat cortex from late fetal to adult stages using reverse transcription-polymerase chain reaction and western blot assays. The primers for NCX1 mRNA targeted the alternative splicing domain to allow differentiation between NCX1 splice variants. Our results show that: (1) only two NCX1 mRNA splice variants (NCX1.5 and NCX1.4) are present in the cortex and their expression is age-dependent; (2) total NCX1 mRNA levels are low in fetal tissue, reach maximum density at postnatal day 8 and substantially decline with further maturation; (3) NCX2 mRNA density is significantly greater than total NCX1 mRNA for all ages and increases markedly during maturation from fetus/neonate to adult; and (4) NCX1 protein expression is lowest in late fetal cortex and reaches maximum levels after 2 weeks postnatally, even though expression levels are not significantly different between newborn and adult animals. Also, we found a similar NCX1 protein trend in the subcortical and cerebellar regions during development. From these data we suggest that NCX1 and NCX2 are differentially expressed in the cortex with a predominance of NCX2 levels during postnatal development. We speculate that the developmental increase in NCX2 expression is responsible for the overall increase in Na(+)/Ca(2+) exchange capacity during maturation.