Objectives: On the one hand neuronal activity results in significant pH shifts in neurons, glia, and interstitial space. On the other hand, a rise in brain pH is associated with increased neuronal excitability, whereas a fall in pH has been shown to have the opposite effect. Thus pH is an important parameter affecting brain function. Several transport mechanisms are involved in the fine-tuning and regulation of extra- and intracellular pH which may be disease relevant. Indeed, a common polymorphism within the neuronal anion exchanger AE3 had been shown to be associated with idiopathic generalized epilepsy. Methods: To better understand the role of bicarbonate transporters for pH regulation in the central nervous system, we have established knockout-mouse models for several members of the SLC4A gene family. Results: The in vivo analysis of our mouse models confirms the important role of this gene family for neuronal pH regulation and neuronal excitability. In addition, analysis of these mouse models allowed to unravel unexpected roles of these proteins e.g. in the secretion of cerebrospinal fluid, the kidney and the retina. Conclusion: More important functions are likely to be unraveled by careful analysis of these mouse models.