Conventional diffusive-based dialysis modalities including high-flux hemodialysis are limited in their capacity to clear middle and large size uremic toxins. Middle molecule substances are recognized as pathogenic substances implicated in the genesis of accelerated atherosclerosis. Convective methods, mimicking glomeruli filtration of native kidneys, are required to enlarge the molecular weight spectrum of solutes removed. By combining diffusive and convective solute clearances, HDF offers at the present time the highest dialysis efficiency method with the more biocompatible profile. Instantaneous dialyzer clearance does not reflect solute mass removal when body clearance is concerned. Intracorporeal resistance to solute clearance is the main barrier to solute removal. Increasing treatment time and/or frequency of sessions in hemodiafiltration is the only way to overcome body barriers generated from patient/dialysis interaction. A dialysis dose based on normalized middle molecules clearance using Beta2-microglobulin as surrogate marker should be considered as a new adequacy target.