The potassium-sparing diuretic amiloride has proven to be a useful pharmacological tool for elucidating the molecular basis and physiological regulation of facilitated sodium entry in tissues and cells. There are two general classes of Na+ transport mechanisms which are sensitive to this drug: 1) a conductive Na+ entry pathway found in electrically high resistance epithelia and 2) a Na+-H+ electroneutral exchange system found in certain leaky epithelia such as the renal proximal tubule. This latter system is also found in many different cellular preparations and seems to function in cell proliferation and differentiation, volume regulation, and intracellular pH regulation. In these cells, this exchange pathway becomes operational usually after some external stimuli. Much higher concentrations of amiloride are required to inhibit the exchange pathway than those required to inhibit the Na+ entry pathway. This drug is the most potent and specific inhibitor of Na+ entry found to date and thus affords the opportunity to be used as a label for the isolation of these transport moieties.