The apical (outward-facing) membranes of high-resistance epithelia contain Na+ channels, traditionally identified by their sensitivity to block by the K(+)-sparing diuretic amiloride. Such channels have been characterized in amphibian skin and urinary bladder, renal collecting duct, distal colon, sweat and salivary glands, lung, and taste buds. They mediate the first step of active Na+ reabsorption and play a major role in the maintenance of electrolyte and water homeostasis in all vertebrates. In the past, these channels were classified according to their biophysical and pharmacological properties. The recent cloning of the three homologous channel subunits denoted alpha-, beta-, and gamma-epithelial Na+ channels (ENaC) has provided a molecular definition of at least one class of amiloride-blockable channels. Subsequent studies have established that ENaC is a major Na(+)-conducting pathway in both absorbing and secretory epithelia and is related to one type of channel involved in mechanosensation. This review summarizes the biophysical characteristics, molecular properties, and regulatory mechanisms of epithelial amiloride-blockable Na+ channels. Special emphasis is given to recent studies utilizing cloned ENaC subunits and purified amiloride-binding proteins.