Hemodiafiltration (HDF) is a well-recognized treatment modality that offers a way of optimizing renal replacement therapy efficacy of end-stage renal disease (ESRD) patients. On-line production of substitution fluid by the ‘cold sterilization’ process (ultrafiltration) gives access to an unlimited amount of sterile and non-pyrogenic IV grade solution. This advantageous low-cost solution may therefore be employed to develop various forms of high-flux HDF modalities (ol-HDF). High-flux post-dilutional HDF (post-HDF) has mainly been used in clinical practice since it offers the most efficient and best compromise between diffusive and convective clearances. Nowadays, the new targets in anemia correction have created hemorheological conditions that render high filtration rate more difficult to achieve and/or at the expense of higher transmembrane pressure. To overcome this new challenging condition and keeping the same concept, it has been proposed to develop alternative modalities with various sites of fluid substitution (predilution, mixed pre-post with various percentages) in HDF. In this presentation we discuss the benefits of using pre-HDF and show how to match performances with post-HDF. Potential advantages of new ol-HDF options (pre-, mixed and mid-dilution) that are advocated have to be demonstrated in clinical trials. On-line HDF is a multipurpose treatment method that is employed to improve care and outcomes of ESRD patients. Due to its versatility, ol-HDF should be considered as a technical platform permitting to personalize and tailor treatment to patients’ needs. The mode of substitution (post-, pre-, mixed or mid-dilution) should be established according to hemorheological conditions of the individual patient.