The final adjustment of renal sodium and calcium excretion is achieved by the distal nephron, in which transepithelial ion transport is under control of various hormones, tubular fluid composition, and flow rate. Acquired or inherited diseases leading to deranged renal sodium and calcium balance have been linked to dysfunction of the distal nephron. Diuretic drugs elicit their effects on sodium balance by specifically inhibiting sodium transport proteins in the apical plasma membrane of distal nephron segments. The identification of the major apical sodium transport proteins allows study of their precise distribution pattern along the distal nephron and helps address their cellular and molecular regulation under various physiological and pathophysiological settings. This review focuses on the topological arrangement of sodium and calcium transport proteins along the cortical distal nephron and on some aspects of their functional regulation. The availability of data on the distribution of transporters in various species points to the strengths, as well as to the limitations, of animal models for the extrapolation to humans.