The precise adaptation of renal sodium excretion to systemic needs is to a large extent achieved by the regulation of sodium re-absorption in the aldosterone-sensitive distal nephron. Transcellular sodium re-absorption by the segment-specific cells of the aldosterone-sensitive distal nephron (often called principal cells) is mainly controlled at the level of the expression and activity levels of the epithelial sodium channel, the apical amiloride-sensitive sodium influx pathway. Recent investigations have identified the first early aldosterone-induced proteins that act on epithelial sodium channel function in expression systems. Indirect evidence suggests that one of these aldosterone-induced proteins, the serum- and glucocorticoid-inducible protein kinase SGK1, plays a central integratory role in the control of epithelial sodium channel surface expression and activity, also in the mammalian kidney. Gene-modified animals lacking epithelial sodium channel subunits or expressing mutant subunits have substantiated the central role of the epithelial sodium channel in sodium re-absorption and blood pressure control, as well as for neonatal lung liquid clearance. Mice overexpressing or lacking specific hormones or their receptors have been used to study their role in sodium transport regulation, but the study of mouse physiology appears to lag behind the generation of gene-modified mice. Nonetheless, these new animal models have had a strong impact on research, by stimulating the integration of knowledge and techniques learned from reductionistic molecular approaches into tissue and animal studies, thus breaking down barriers and stimulating collaborations.