The predominant organic solutes of the renal medulla have been hypothesized to osmotically balance extracellular NaCl and protect macromolecular function from the adverse effects of urea. The evidence for their long- and short-term physiologic significance in vivo has been reviewed. The organic solutes decrease acutely in response to diuresis with a time course similar to that observed for inorganic ion fluxes and therefore probably play an important role in short-term volume regulation. However, because organic solutes are slow to accumulate (even in the presence of high urea and sodium concentrations), their significance to the short-term physiologic function of renal medullary epithelia is in doubt and needs further investigation. The organic solutes may be more important to the long-term function and survival of renal medullary cells.