•Subfornical organ is the primary locus of Na+-level sensing in the brain.•Nax is the Na+-level sensor to control thirst and salt appetite.•Anaerobic glycolysis is Na+-level dependently activated in the glial cells via Nax.•Lactate is a gliotransmitter that enhances GABAergic firing in the subfornical organ.•Autoantibody production to the subfornical organ causes essential hypernatremia. The brain monitors conditions of body fluids and levels of circulating neuroactive factors to maintain the systemic homeostasis. Unlike most regions in the brain, circumventricular organs (CVOs) lack the blood–brain barrier, and serve as the sensing center. Among the CVOs, the subfornical organ (SFO) is the sensing site of Na+ levels in body fluids to control water and salt intake. The SFO harbors neuronal cell bodies with a variety of hormone receptors and innervates many brain loci. In addition, the SFO harbors specialized glial cells (astrocytes and ependymal cells) expressing Nax, a Na+-level-sensitive sodium channel. These glial cells wrap a specific population of neurons with their processes, and control the firing activities of the neurons by gliotransmitters, such as lactate and epoxyeicosatrienoic acids (EETs), relevant to water/salt-intake behaviors. Recent advances in the understanding of physiological functions of the SFO are reviewed herein with a focus on the Na+-sensing mechanism by Nax.