The epithelial sodium channel (ENaC) was cloned just 10 years ago. Since that time, the study of human monogenic diseases (pseudohypoaldosteronism type 1 [PHA-1] and Liddle syndrome), as well as mouse models mimicking salt-losing syndromes (PHA-1) or salt-sensitive hypertension (Liddle syndrome), have greatly contributed to our understanding of the function of ENaC in vivo. In this brief review, I will first discuss ENaC as a limiting factor in the control of ionic composition of the extracellular fluid and then, more specifically, the activation of ENaC by membrane-bound serine proteases. Recent in vitro and in vivo experiments indicate that membrane-bound serine proteases (channel activating proteases [CAP-1, -2, or-3]) may be of critical importance in the activation of ENaC in different organs, such as the kidney, the lung or the cochlea.