TonEBP is a member of the Rel family of transcriptional activators, distinct from other members NFkappaB and NFAT. In the medulla of mammalian kidney, TonEBP is a local differentiation factor that stimulates the transcription of several genes. The activity of TonEBP is regulated by changes in diuretic status mainly at the level of nucleocytoplasmic distribution. Some of the genes stimulated by TonEBP encode transporters and a synthetic enzyme for cellular accumulation of compatible osmolytes, which protect cells from the deleterious effects of hypertonicity by lowering cellular ionic strength. Other genes include the vasopressin-regulated urea transporters that play a key role in building up high urea concentrations in the renal medulla during antidiuresis and a heat shock protein 70 that protects cells from the deadly effects of urea. TonEBP is also abundantly expressed in other tissues such as brain, heart, liver, and activated T-cells. TonEBP plays a significant role in immunity by stimulating several cytokine genes in the T-cells. A lot more needs to be learned about the genes regulated by TonEBP and signaling pathways from hypertonicity to the activation of TonEBP.