The use of gene-modified mouse models allows the experimental in vivo analysis of specific gene defects at the level of target cells. With respect to the epithelial sodium channel and some of its regulatory proteins, gene-modified models that control gene defects in a time- and tissue-dependent conditional or constitutive manner have been generated. The combination of molecular and physiologic approaches in these mouse models increases the understanding of the complex regulation and the cell signaling cascades involved in Na(+) transport in target cells and may ultimately provide new insights into the pathophysiology of renal Na(+) retention and BP regulation. This review summarizes and discusses the gene-targeting approaches that have been applied to the epithelial sodium channel and its regulatory proteins.