Water deprivation leads to depletion of both the intracellular and extracellular compartments. The resulting cellular dehydration and extracellular dehydration stimulate thirst and the secretion of vasopressin. The cellular stimulus is thought to arise from a change in volume and hence in the hydration status of specific osmoreceptor cells located in the anterior hypothalamus. Thus, reduction in cell volume because of either water deprivation or administration of hyperosmolar solutions of solutes that cannot penetrate cell membranes would stimulate thirst and vasopressin secretion, whereas an increase in cell volume caused by water intake would inhibit these responses. An alternative theory proposes that receptors in the region of the third cerebral ventricle that are sensitive to the concentration of sodium in cerebrospinal fluid are responsible for stimulating the responses to cellular dehydration. Both theories must account for the fundamental observation that NaCl, which does not penetrate cells, and urea, which does, are both excluded from the brain by the blood-brain barrier, and thus both solutes cause cerebral dehydration. However, NaCl stimulates drinking and vasopressin secretion but urea does not. The periventricular sodium receptor theory is not compatible with this observation. An osmoreceptor theory is compatible with the data if it is assumed that the receptors reside outside the blood-brain barrier, for example, in a circumventricular organ.