Despite the availability of calcitriol and recombinant erythropoietin to replace two major endocrine functions of the kidneys, mortality in chronic hemodialysis patients remains substantially higher than that in the general population. This suggests that most, if not all, patients are underdialyzed. While increasing small solute clearance by dialysis using urea kinetics as a guide improves clinical outcome, ‘adequate’ treatment using current techniques is only an arbitrary definition, since solute removal by dialysis remains far inferior to that of the normal native kidneys. In recent years, significant advances have been made in the structural and functional characterization of toxic uremic solutes that are in the higher molecular size range (‘middle molecules’). Several lines of evidence suggest that, in addition to small solutes, removal of middle molecules is also advantageous. The potential beneficial effects of synthetic high flux hemodialysis membranes are probably attributed to both their solute clearance profiles as well as their biocompatibility characteristics.