Within the last decade it has become increasingly clear that dysregulated expression, splicing, and/or function of ion transporters and channels occurs in all cancers and contributes importantly to cancer development (1,2). Being linked to essentially all of the widely accepted hallmarks of cancer, ion transporters and channels represent novel therapeutic, diagnostic and prognostic targets. Our research group has focused in particular on dysregulation of pH regulatory ion transport in breast cancer. A fundamental property of solid tumors is a markedly altered pH-profile compared to normal tissues, with acidic extracellular, and often alkaline intracellular pH (pHi). This at least in part reflects their upregulated glycolytic metabolism, necessitating increased acid extrusion to maintain survival. Whereas the Na+/H+ exchanger NHE1 (SLC9A1) has until recently received the majority of the attention in the context of pH (dys)regulation in cancer, our recent findings indicate that the Na+HCO3- cotransporter NBCn1 (SLC4A7) may be of substantial importance in this context. Expression of a constitutively active, truncated form of the ErbB2/HER2 receptor (ΔNErbB2) greatly increased pH regulatory capacity in MCF-7 human breast cancer cells, in a manner mediated by NHE1 and NBCn1 (3). After ΔNErbB2 expression or stimulation of wild-type ErbB receptors, NBCn1 was strongly upregulated at the mRNA and protein levels, and NHE1 was phosphorylated at Ser703, a known target for the 90 kDa Ribosomal S6-Kinase (p90RSK). The regulation of the NBCn1 promoter by ErbB2 signaling involves Src, Extracellular Signal Regulated Kinase (ERK), and Phosphatidyl-Inositol-3 Kinase (PI3K)-Akt signaling, as well as the transcription factor Krüppel-like 4 (KLF4), which has been assigned important and context-dependent pro- and anti-oncogenic roles in various cancers. In 2D cultures of MCF-7 cells NHE1 localized strongly to invadopodial rosettes, where it colocalized with the invadopodial markers cortactin, F-actin and phospho-Tyr416-Src, as well as with its known binding partners, ezrin and radixin (4). NHE1 inhibition or siRNA-mediated NHE1 knockdown potently sensitized ΔNErbB2-MCF-7 cells to cisplatin-induced apoptosis and enhanced their adhesion and 2D migration on collagen-I (3,4). Using 2D- and 3D cell culture models mimicking various aspects of the tumor microenvironment we show that the regulation and localization of NHE1 and NBCn1 are dependent on different microenvironmental factors, and that the role of NBCn1 may become more prominent in 3D culture. Finally, using matched sets of patient tissue we show that NHE1 and NBCn1 are upregulated in primary breast carcinomas and lymph node metastases compared to normal breast tissue, and we demonstrate that Na+HCO3- cotransport is a major determinant of pHi regulation in freshly dissected human breast tumors (5). In conclusion, expression and activity of the two major pH regulatory ion transporters NBCn1 and NHE1 are altered in human breast cancer, resulting in altered pH regulation. NBCn1 expression is strongly sensitive to ErbB receptor activity, and NHE1 regulates chemotherapy sensitivity and cell motility. We suggest that NHE1 and NBCn1 are potential targets in breast cancer diagnosis and/or treatment.