Amiloride-sensitive Na+ channels constitute a new class of proteins known as the ENaC-Deg family of ion channels. All members in this family share a common protein structure but differ in their ion selectivity, their affinity for the blocker amiloride, and in their gating mechanisms. These channels are expressed in many tissues of invertebrate and vertebrate organisms where they serve diverse functions varying from Na+ absorption across epithelia to being the receptors for neurotransmitters in the nervous system. Here, we review progress made during the last years in the characterization, regulation, and cloning of new amiloride-sensitive Na+ channels.