The osmolality of the mammalian kidney medulla is very high. The high osmolality provides the driving force for water reabsorption and urinary concentration, key functions of the kidney for maintaining proper body fluid volume and blood pressure. Salt and urea are the major solutes in the renal medullary interstitium. Unfortunately, high salt (hypertonicity) causes DNA damage and cell death. In response, the renal medullary cells adapt to the hypertonicity by accumulating compatible osmolytes. A regulatory protein, tonicity-responsive enhancer binding protein (TonEBP), plays a central role in the accumulation of these compatible osmolytes by stimulating genes whose products either actively transport or synthesize the appropriate osmolytes. TonEBP is active under isotonic conditions. It responds to both an increase and a decrease in ambient tonicity, in opposite directions, which involves changes in its abundance and nucleocytoplasmic distribution. In the kidney medulla, however, nucleocytoplasmic distribution is the major site of control, under normal conditions of diuresis and antidiuresis.