The epithelial sodium channel (ENaC) is localized in the apical membrane of epithelial cells and is the rate limiting step for sodium absorption in a number of epithelial tissues including the aldosterone-sensitive distal nephron, respiratory epithelia, distal colon, sweat and salivary ducts. In the kidney ENaC is critically important for the maintenance of body sodium balance [1]. This is evidenced by gain-of-function mutations of ENaC which cause a severe form of arterial hypertension known as Liddle’s syndrome. Increased ENaC activity may also contribute to the pathophysiology of cystic fibrosis (CF). This is supported by the observation that airway-specific over-expression of the β-subunit of ENaC in mice causes airway surface liquid depletion and CF like lung disease. Loss-of-function mutations of ENaC cause pseudohypoaldosteronism type I (PHA1), a disease characterized by renal salt wasting. ENaC is a member of the ENaC/degenerin family of ion channels which also includes the acid sensing ion channel ASIC1. The recently published crystal structure of chicken ASIC1 suggests that ENaC is a heterotrimer. Each subunit of ENaC contains two transmembrane domains, a large extracellular domain, and short intracellular amino and carboxyl termini. Three well characterized ENaC subunits (αβγ) are thought to form the trimeric channel. In humans an additional δ-subunit (δ-ENaC) exists which can functionally replace the α-subunit in heterologous expression systems. So far little is known about the physiological function of the δ-subunit which is expressed in a wide range of tissues. The tissue-specific regulation of ENaC by hormones and other factors is highly complex [1]. A unique feature of ENaC regulation is its proteolytic processing thought to be critical for channel activation under physiological and pathophysiological conditions [2]. However, at present the precise molecular mechanism of proteolytic channel activation remains unclear. The channel is in its mature and active form in its cleaved state, but there is evidence for the presence of both cleaved and non-cleaved ENaC in the plasma membrane. Membrane-bound and/or secreted proteases activate ENaC by cleaving specific sites in the extracellular domains of the α- and γ-subunits but not the β-subunit. Putative cleavage sites for furin, prostasin, plasmin, and elastase have been described. Cleavage at these sites probably results in the release of inhibitory peptides. This presumably activates the channel by changing its conformation. We showed that cleavage of the γ-subunit is particularly important for the proteolytic activation of near-silent channels [3] and that the δ-subunit is also proteolytically processed [4]. Most of our knowledge about ENaC activation by extracellular proteases stems from studies in model system like Xenopus laevis oocytes and cultured cells. However, functional evidence is emerging that ENaC activation by extracellular proteases can occur in native tissue. Indeed, we demonstrated that trypsin can activate ENaC in microdissected mouse distal nephron [5]. In nephrotic syndrome filtered plasminogen is converted to plasmin by tubular urokinase-type plasminogen activator. We have shown that plasmin activates ENaC [6]. Thus, ENaC activation by plasmin may contribute to sodium retention in nephrotic syndrome. Moreover, ENaC activation by locally generated proteases may aggravate symptoms of CF during acute respiratory infections. Furthermore, ENaC may be a modifier gene in patients with CF. Indeed, ENaC polymorphisms with a gain-of-function effect have been identified in patients with atypical CF [7]. At present it is unclear why some gain-of-function mutations of ENaC cause Liddle’s syndrome while others cause CF-like pulmonary symptoms without overt renal disease. Organ specific differences in proteolytic ENaC processing may be responsible for the development of different disease phenotypes. However, the (patho-)physiologically relevant proteases for ENaC activation, their regulation and their specific cleavage sites remain to be determined.