Leak K⁺ currents contribute to the resting membrane potential and are important for modulation of neuronal excitability. These K⁺ channels are often referred to as “two-pore-domain” channels because of their predicted topology, which includes 4 transmembrane segments and two pore-forming regions in each subunit. They are open rectifiers and allow the passage of large outward currents under conditions of high internal and low external K⁺. In general, they show little voltage- and time-dependence. Two-pore-domain, or tandem-pore potassium channels are modulated by a host of different endogenous and clinical compounds such as neurotransmitters and anesthetics, and by physicochemical factors such as temperature, pH, oxygen tension, and osmolarity, and have multiple roles in CNS function. They also are subject to long-term regulation by changes in gene expression. At least 15 two-pore-domain channel genes from the human genome have been described. For 11 of these genes, heterologous expression leads to functional channel activity at the plasma membrane[1],[2],[3].