The safety of online hemodiafiltration (ol-HDF) relies on very strict rules of use. The use of ultrapure water to feed an ol-HDF machine is a basic requirement for ol-HDF. Technical aspects and microbial monitoring have been precisely described in the European Best Practice Guidelines. Specifically designed and certified ol-HDF machines are needed. All these machines share the production of substitution fluid by the cold sterilization process of fresh dialysate based on ultrafilters. Hygiene handling is a crucial measure to ensure permanent safety of the ol-HDF system. Frequent disinfection of the water treatment system and dialysis machine, destruction of biofilm by chemical agents and/or thermochemical disinfection, change of filters at regular intervals, and maintenance of a permanent circulation of water are among the basic measures required to ensure ultra-purity of water and dialysis fluid. Optimal performances of ol-HDF require the use of high blood flow (300-400 ml/min), highly permeable and adequately sized hemodiafilters, a high volume of substitution (5-6 l/h) and high dialysate flow (500 ml/min). The site and type of substitution (pre-, post-, mixed, and mid-dilution) should be customized to each patient according to its blood hemorheology and its filtration fraction limitation (transmembrane pressure). All attempts should be made to maximize the fluid volume exchange per session (convective dose) in any cases. The treatment schedule in terms of session duration and weekly frequency need to be adjusted individually to improve hemodynamic tolerance, to facilitate correction of fluid overload and to increase dialysis dose (for middle-sized solutes) in order to reduce circulating levels of major uremic toxins. ol-HDF is the more advanced form of renal replacement therapy offering high efficiency over a large spectrum of toxins, high biocompatibility profile and high flexible modality. ol-HDF may help to improve global care of chronic kidney disease patients and may be considered the renal replacement therapy of the future.