Asbjørg Stray-Pedersen, Jan-Maarten Cobben, Trine E. Prescott and colleagues study the roles of voltage-independent “leak” channels in human disease. Their analysis is focused on UNC80 which is a large component of the NALCN sodium-leak channel complex that regulates the basal excitability of the nervous system. Their findings demonstrate the fundamental significance of UNC80 and basal ionic conductance to human health.