Current understanding of the benefits of daily and nocturnal hemodialysis is limited by the designs used in previous studies which tested these therapies. There is increasing momentum to evaluate these therapies in randomized controlled trials. By establishing the efficacy, safety and delivery of daily and nocturnal hemodialysis, such trials will guide policy and funding decisions regarding the role of these therapies in the treatment of end-stage renal disease. However, in designing trials that fulfill these goals, many questions arise. What study population should be used? How should the intervention be defined? Which outcomes should be evaluated? Several methodological issues particular to trials of frequent dialysis require additional consideration. The ‘ideal’ trial in terms of methods must be balanced against the feasibility of implementation and budgetary constraints. Here, we explore some of these issues.