Analyses based on the National Cooperative Dialysis Study (NCDS) provided the impetus for routine quantification of delivered dialysis dose in hemodialysis practice throughout the world, by suggesting minimum targets for small solute (urea) clearance. Morbidity and mortality in dialysis populations remain high despite many technological advances in dialysis delivery. A number of observational studies reported association between higher dose of dialysis as measured by Kt/V urea or urea reduction ratio with lower mortality risk. During the 1990s, a steady increase in dialysis dose and a modest reduction in mortality on dialysis were observed. However, observational studies only reveal associations and are limited by selection bias and confounding. The Kidney Disease Outcomes Quality Initiative guidelines on dialysis adequacy are based on results of observational studies and expert opinion. Since the NCDS, the HEMO Study was the first major randomized clinical trial designed to study the effect of dose of dialysis and dialyzer flux on patient outcomes. Despite adequate separation of dose and flux, however, results of the trial did not prove a beneficial effect of higher dose. The Dialysis Outcomes and Practice Patterns Study (DOPPS), in a major international effort designed to examine the effect of practice patterns on outcomes, has made significant contributions to the topic of dialysis dose. The following review critically examines data from observational studies, including the DOPPS, and from the HEMO Study, emphasizing important lessons from both, and discusses future paradigms for achieving dialysis adequacy to improve patient outcomes.