Water gain in the brain consequent to hyponatremia is counteracted by mechanisms that initially include a compensatory displacement of liquid from the interstitial space to cerebrospinal fluid and systemic circulation and subsequently an active reduction in cell water accomplished by extrusion of intracellular osmolytes to reach osmotic equilibrium. Potassium (K+), chloride (Cl-), amino acids, polyalcohols, and methylamines all contribute to volume regulation, with a major contribution of ions at the early phase and of organic osmolytes at the late phase of the regulatory process. Experimental models in vitro show that osmolyte fluxes occur via leak pathways for organic osmolytes and separate channels for Cl- and K+. Osmotransduction signaling cascades for Cl- and taurine efflux pathways involve tyrosine kinases and phosphoinositide kinases, while Ca2+ and serine-threonine kinases modulate K+ pathways. In-depth knowledge of the cellular and molecular adaptive mechanisms of brain cells during hyponatremia contributes to a better understanding of the associated complications, including the risks of inappropriate correction of the hyponatremic condition.