Favorable clinical outcomes related to morbidity, mortality, patient well-being, laboratory biomarkers, and medication use have been reported with in-center nocturnal hemodialysis (INHD); nevertheless, it is not entirely clear how much patient selection or physiologic mechanisms related to better fluid management and phosphorus (and calcium) metabolism may explain these outcomes. There are indications that INHD may be a preferred treatment option in specific cases, such as in patients with high interdialytic weight gain, poor tolerance to high ultrafiltration rate, hyperphosphatemia, or for those patients who work or go to school during the day. In the era of the new prospective payment system where quality standards become intertwined with reimbursement, an INHD program may be a useful method to help attain quality goals in facilities that have patients with unfavorable case-mix. The experience of the past decade has shown INHD to be safe and well tolerated by patients. The growth of INHD therapy is a testament to sustainability and feasibility of this treatment option. Prospective clinical trials are needed in this area. If the promise of INHD is fulfilled, it may also prove to be a valuable option for potential success of Accountable Care Organizations where providers need to assume responsibility for more patient-centered care and improvement in clinical outcomes. In summary, based on the current experience, INHD is a viable and valuable option as an additional, alternative hemodialysis (HD) regimen to conventional HD.