Online production of substitution fluid by 'cold sterilization' (ultrafiltration) of dialysis fluid gives access to virtually unlimited amounts of sterile and nonpyrogenic solution. The incorporation of the online hemodiafiltration (ol-HDF) module into the dialysis proportioning machine hardware simplifies the handling procedure, secures the process by keeping the safety regulation of the monitor and offers virtually unlimited amounts of sterile and nonpyrogenic substitutive solution. The safety of the ol-HDF relies upon use of ultrapure water and strict and permanent highly hygienic rules of use. The use of a specifically designed certified HDF machine is also mandatory. Several forms of ol-HDF have been developed and used to cover specific clinical needs of chronic kidney disease patients. Conventional ol-HDF are classified according to the mode of substitution as post-, pre- and mixed dilution. Alternative-based ol-HDF incorporate push/pull HDF, double high-flux HDF, paired HDF and middilution HDF. A very simple description of these methods is provided in this section. Best clinical practices are summarized in this section to optimize performances of ol-HDF and maximize the safety of the method. It is noteworthy to stress the important role of blood flow, fluid volume exchange, hemodiafilter performances and duration of sessions in the overall treatment efficacy. It is also crucial to insist on the importance of strict hygienic handling, microbiology monitoring and the quality assurance process to ensure the safety of the method. In addition, ol-HDF offers the best technical platform to develop new therapeutic strategies such as daily treatment, total automation of priming and cleansing procedures and biofeedback volume control.