Mammalian genomes contain 10 SLC4 genes that, between them, encode three Cl–HCO₃ exchangers, five Na⁺-coupled HCO₃ transporters (NCBTs), one reported borate transporter, and what is reported to be a fourth Cl–HCO₃ exchanger. The NCBTs are expressed throughout the body and play important roles in maintaining intracellular and whole-body pH, as well as contributing to transepithelial transport processes. The importance of NCBTs is underscored by the genetic association of dysfunctional NCBT genes with blindness, deafness, epilepsy,hypertension and metal retardation. Key to understanding the action and regulation of NCBTs is an appreciation of the diversity of NCBT gene products. The transmembrane domains of human NCBT paralogs are 50–84% identical to each other at the amino acid level, and are capable of a diverse range of actions, including electrogenic Na/HCO₃ cotransport (i.e. NBCe1 and NBCe2) and electroneutral Na/HCO₃ cotransport (i.e. NBCn1 and NBCn2), as well as Na⁺-dependent Cl–HCO₃ exchange(i.e. NDCBE). Furthermore, by the use of alternative promoters and alternative-splicing events, individual SLC4 genes have the potential to generate multiple splice variants (as many as 16 in the case of NBCn1), each of which could have unique temporal and spatial patterns of distribution, unitary transporter activity (i.e. flux mediated by one molecule), array of protein-binding partners, and complement of regulatory stimuli. In the first section of this review, we summarize our present knowledge of the function and distribution of mammalian NCBTs and their multiple variants. In the second section of this review we consider the molecular consequences of NCBT variation.