Purification of high molecular uremic toxins by conventional hemodialysis is limited. It remains associated with a high morbidity and excessively high mortality. Online hemodiafiltration using a high permeability hemodiafilter, an ultrapure dialysate, and which tends to maximize substitution volumes, provides a high efficiency and low bio-incompatibility renal supplementation. Regular use of online hemodiafiltration is associated with reduced morbidity (reduction of intradialytic hypotension episodes, improved blood pressure control, reduced inflammatory profile, better anemia correction and prevention of β2-microglobulin-associated amyloidosis). Recently, several cohort studies have shown that hemodiafiltration with high substitution volume was associated with a significant reduction in mortality. Randomized studies have been conducted in Europe to confirm these facts. The high safety of online hemodiafiltration has been confirmed in clinical practice by prospective studies. Online hemodiafiltration has reached its full maturity phase and is expected to represent the new standard of renal replacement therapy.