Hemodiafiltration appears to be the most effective technique of renal replacement therapy but several drawbacks are not counterbalanced by significant advantages. Although optimal transfer for both small and middle molecules can be achieved, there is no difference in mortality risk between HDF and HD patients. The infusion of a large amount of dialysate containing residual acetate of 2–7 mmol/l could lead to impaired cardiac contractile functions and carbonyl stress whereas loss of amino acids and water-soluble vitamins along with high UF rate could lead to malnutrition. Moreover, as substitution fluid is prepared on-line, contaminated fluid could be inadvertently infused to patients. Stringent maintenance rules are required for the production of sterile and non-pyrogenic dialysis solutions. Finally, daily hemodialysis could be the most promising mode of renal replacement therapy since it leads to a more stable ‘milieu interieur’ than other techniques whatever the mode of solutes removal when performed three times a week.