Nocturnal home hemodialysis (NHD) is the most intensive dialysis strategy among dialytic renal replacement options and is receiving increased attention as more research reveals its physiologic restorative potential compared with conventional hemodialysis; however, a significant gap in knowledge remains concerning the predictors of program success and the clinical outcomes of NHD. This review aims to highlight the methodologic strengths and pitfalls of various study designs as they pertain to NHD research and lays the foundation for the CANandian Slow Long nightly ExtEnded dialysis Programs (CAN-SLEEP), a multicenter NHD research network aimed to facilitate investigation of NHD.