Two-pore domain potassium (K2P) channels are expressed in cells throughout the body and give rise to leak potassium currents which control the excitability of these cells. Although not inhibited by classical potassium channel-blocking drugs, such as tetraethylammonium and 4-aminopyridine, K2P channels are regulated by a diverse array of pharmacological mediators. There are six main families of K2P channels and among these certain members of the TREK family (ie, TREK-1 and TREK-2) are activated by general anesthetic agents such as halothane, xenon and nitrous oxide. In addition, all members of the TREK familyare activated by neuroprotective agents, such as riluzole, polyunsaturated fatty acids and lysophospholipids, suggesting that these channels play an important role in neuroprotection. TREK channels are also inhibited by chlorpromazine, local anesthetics and the antidepressant fluoxetine. Furthermore, all members of the TASK family are inhibited by cannabinoids and local anesthetics, and TASK-3 is selectively inhibited by ruthenium red. Thus, the diversity and physiological importance of K2P channels suggest that the development of selective compounds to target these proteins has therapeutic potential for CNS disorders such as stroke, depression and epilepsy.