As part of the urinary concentrating mechanism, renal inner medulla cells may be exposed to extremely variable NaCl and urea concentrations that can reach very high levels. A number of studies, reviewed herein, aim to understand how such osmotic stress affects the cells and what protective mechanisms might exist. The majority of these studies are done on inner medullary epithelial cells that grow continuously in tissue culture (mIMCD3). Cells grown at 300 mosmol/kg survive increase to 500 mosmol/kg by adding NaCl or urea, but only after a growth arrest of approximately 24 h. At a higher osmolality (650-700 mosmol/kg) most cells die within hours by apoptosis. The cells both in vitro and in vivo adapt to high osmolality by a number of mechanisms, including accumulation of variety of organic osmolytes and induction of heat shock proteins. The cell cycle delay results from blocks at the G1 and G2/M checkpoints and slowing during S. After adding NaCl, but not urea, the amount and transcriptional activity of p53 (the tumor suppressor protein) increases. The p53 is phosphorylated on ser-15 and is transcriptionally active at 500 mosmol/kg (associated with cell survival), but not at 700 mosmol/kg (associated with apoptosis). Reduction of p53 expression by p53 antisense oligonucleotide increases sensitivity of renal cells in culture to hyperosmotic stress caused by NaCl. The possible mechanisms of the protection action of p53 against hypertonic stress are discussed.