This Editorial Review summarizes certain considerations relevant to the mechanism(s) of isotonic fluid absorption by the mammalian proximal nephron. Recent evidence indicates that the paracellular pathway in this epithelium has a low diffusion resistance. Therefore it is possible that lateral intercellular spaces are in diffusion equilibrium with the peritubular medium. For such a circumstance, the driving forces for isotonic fluid absorption may reside in external solutions. But since the hydraulic conductance of mammalian proximal tubules is remarkably high, the effective osmotic pressure gradient between luminal and pertibular solutions required to drive isotonic fluid transport is relatively small. In the mammalian proximal nephron, effective luminal hypotonicity may provide the driving force for isotonic fluid transport. At least two mechanisms could account for the development of effective luminal hypotonicity. First, preferential absorption of bicarbonate results in a rise of luminal Cl- concentration. And because proximal tubules are more permeable to Cl- than to HCO3-, there develops a driving force for isotonic fluid transport. Second, trivial degrees of luminal hypotonicity may develop attendant on active Na+ absorption. We provide evidence that, of these two mechanisms, axial anion asymmetry is the dominant force for isotonic fluid transport.