An adequate dose of hemodialysis is currently defined by the Kidney Disease Outcomes Quality Initiative (K/DOQI) and European guidelines as a delivered single-pool urea Kt/V (spKt/V) of 1.2 and 1.4, respectively. Results from several studies, in particular the Hemodialysis (HEMO) study, have largely supported the legitimacy of these guidelines, although they may need to be altered or amended for certain patient subgroups. This review discusses several potential changes to current guidelines based on recent clinical outcome studies. The following questions are addressed: 1) Should the dialysis dose for low molecular weight water-soluble solutes (i.e., urea) be normalized by the body distribution volume for urea? 2) Should spKt/V or equilibrated Kt/V (eKt/V) be used for routine monitoring of the hemodialysis dose? 3) Should the dialysis dose for small solutes be dependent on gender? 4) Should the dialysis dose for middle molecules be used in clinical practice? 5) What should be the dialysis dose when using hemodialysis treatment strategies that are more frequent than thrice weekly?