Aquaporins constitute a family of water channels that regulate the transport of water in essentially all organs, including the kidney, gastrointestinal tract, secretory glands, inner ear, nervous system, and muscle.1–3 Because of his seminal discovery of aquaporins as the long-sought water channels,1 Peter Agre of Johns Hopkins University was awarded the Nobel Prize in Chemistry in 2003. Aquaporin-4 (AQP4) is the main aquaporin in the brain and is expressed in highest density in the perivascular and subpial astrocyte end-feet. Aquaporin-4 is a critical component of an integrated mechanism of regulation of cell volume and potassium (K+) homeostasis. Aquaporin-4 has been implicated in several neurologic conditions, including cerebral edema and seizures, and is the target of autoimmune attack in neuromyelitis optica (NMO). Recent studies on expression of and regulation of AQP4 provide testable hypotheses on the mechanisms of neural damage and make AQP4 a potential therapeutic target in these and other conditions. Aquaporins are water channels that consist of four identical subunits, each with six membrane-spanning α-helices.2,3 Aquaporin-4 is the most abundant aquaporin in the brain and is concentrated at glial–fluid interfaces, particularly in the perivascular and subpial end feet of the astrocytes (figure 1). Aquaporin-4 is also present on ependymal cells, and in low levels, on brain endothelial cells.3 The polarized distribution of AQP4 in the perivascular and subpial domains of the astrocytic plasma membrane results from its interaction with cytoskeleton and extracellular matrix proteins as part of the dystroglycan complex.4 At the astrocyte end foot process, AQP4 co-localizes with the …