Virtually all cells respond to hypertonicity by accumulating certain small organic solutes (compatible osmolytes) that, in contrast to intracellular ions, do not perturb macromolecular function. Several important compatible osmolytes are accumulated by coupled transport. Transcription of genes encoding these cotransporters is increased by hypertonicity and a tonicity-responsive enhancer element has been identified. When cells return to an iso-osmotic environment, osmolytes are rapidly lost through a pathway that current evidence indicates may be a volume-sensitive chloride channel.