Hemodialysis (HD) therapy for patients suffering from end-stage renal disease (ESRD) has been a major breakthrough in medicine during the twentieth century. Empirically, the conventional treatment is prescribed as 34.5 h of dialysis, three times a week. However, this prescription is being questioned because of poor patient outcomes including a persistently high death rate. Over the past 30 years, K-t/V-urea has been recognized as the predominant marker of dialysis adequacy. However, other important markers of adequate dialysis are increasingly being recognized, including fluid and phosphate balance, and middle molecule removal. Conventional HD therapy, as it exists today, is limited in its scope to make a significant impact on these markers. Consequently, there is an active debate on novel HD strategies to improve patient outcomes. Recently, two randomized controlled trials (RCTs) have highlighted potential benefits for patients with two such strategies, short or long nocturnal daily dialysis. These two trials did, however, highlight the difficulty in recruiting patients for such studies. A higher rate of blood access-related complications was also reported. Such novel strategies are also limited in their application by a higher economic burden and logistical difficulties. On the other hand, the thrice-weekly nocturnal HD prescription has been associated with excellent clinical results in observational reports published over recent years. Several non-randomized controlled studies support the clinical benefits of this approach. This prescription may overcome the limitations of daily dialysis and offer a potential for improving patient outcomes on HD. Even if the methodology of the latter studies may not be optimal, we underscore the point that this alternative dialysis prescription should be included in the current debate of novel dialysis strategies.