There are two main mechanisms by which the body combats dehydration. Dehydration leads to a decrease in blood volume (hypovolemia) and, consequently, an increase in plasma osmolality (increased solute concentration). The increase in osmolality, in turn, is detected by osmoreceptor neurons in the hypothalamus. Increases in sodium (Na⁺) and chloride (Cl⁻) are potent stimulators of hypothalamic osmoreceptors. Hypothalamic osmoreceptors are located in the circumventricular organ referred to as the organum vasculosum of the lamina terminalis (OVLT). Hypothalamic osmoreceptors then stimulate other hypothalamic neurons (magnocellular neurons), whose cells bodies are in the supraoptic and paraventricular nuclei of the anterior hypothalamus, but whose axon terminals are in the posterior pituitary, to release the antidiuretic hormone (ADH; also known as vasopressin) into the bloodstream. Circulating ADH reaches the kidney collecting ducts to increase water reabsorption and hence water retention. Increased water retention increases the extracellular fluid volume (and blood volume), ultimately bringing plasma osmolality back down to its normal set point of about 295 mOsm/kg. Note that that at the normal plasma osmolality of 295 mOsm/kg, there is baseline secretion of ADH, thus, allowing for dynamic control of ADH release when plasma osmolality increases or decreases.

The second mechanism activated by dehydration is to stimulate thirst in order to ensure that sufficient fluids are ingested to replenish the water lost and to bring the plasma osmolality back down to its normal level. To stimulate thirst, osmoreceptor neurons in the hypothalamus relay information to the cerebral cortex where thirst becomes a conscious sensation. Note that that at the normal plasma osmolality of 295 mOsm/kg, there is baseline stimulation of thirst, and this basic thirst sensation is probably incorporated into daily drinking habits.

In addition, during dehydration, there are peripheral mechanisms that stimulate both ADH secretion and thirst. These mechanisms are primarily in the form of stretch receptors that detect low blood volume (hypovolemia) and are found in the carotid sinus, aortic arch, right atrium of the heart, and juxtaglomerular cells of the kidneys. Under most normal physiological conditions, the activity of hypothalamic osmoreceptors is a stronger regulator of ADH secretion and thirst stimulation.

The plasma osmolality threshold for stimulating ADH secretion from the posterior pituitary is approximately 280 mOsm/kg. The plasma osmolality threshold for stimulating thirst is approximately 290 mOsm/kg. It is important to note that significant individual variability exists in these threshold values. Note that thirst intensity is plotted on an arbitrary scale. Usually, an analog visual scale is used in human studies, where subjects rate thirst intensity. This scale is not equivalent to the scale on the left y-axis for ADH plasma concentration.