The kidney plays a dominant role in maintaining sodium homeostasis. The control of a nearly constant electrolyte composition and osmotic pressure in the extracellular fluids is achieved by well-regulated vectorial salt and water transport processes. Derangement in function of Na(+) transporting proteins is likely to be responsible for a number of clinical disorders of fluid and electrolyte homeostasis. The identification of the genes implicated in sodium reabsorption in the kidney not only allows a detailed analysis of regulation and function of these proteins in vitro but also the generation of genetically engineered mice that constitute valuable mouse models for human diseases. Our review will focus on recent strategies for generating nephron segment-specific knock-outs for the main apical renal Na(+) transporters and channels.