The cells in the renal medulla protect themselves from the extracellular hypertonicity in that region of the kidney by accumulating large amounts of sorbitol, inositol, grycerophosphorylcholine, and betaine. The system is uniquely active in this part of the body, but it represents a throwback to primitive mechanisms by which cells in virtually all organisms, including bacteria, yeasts, plants, and lower animals counteract water stress. In this brief review, we ummarize how these “compatible organic osmolytes” help the renal medullary cells to survive, the mechanisms by which the organic osmolytes are accumulated, and how the accumulation is controlled to adjust for changing extracellular NaCl and urea concentrations. The compatible organic osmolytes are all intermediates in important biochemical pathways, and although the medical consequences are not yet fully worked out, it is already apparent that inappropriate accumulation of these solutes has major pathophysiological consequences.