Most end-stage renal disease patients on maintenance haemodialysis follow the typical schedule of three sessions per week, and thus remain outside dialysis for two short intervals (∼2 days in duration) and for a longer interval (∼3 days) at the end of each week. This pattern was historically enforced more due to calendar logistics and less due to factors related to health and disease. Therefore, it is long hypothesized that the intermittent nature of haemodialysis and the consequent shifts and fluctuations in volume status and metabolic parameters during the dialysis-free periods may pre-dispose patients to several complications. Recent large-scale observational studies in haemodialysis patients link the first week-day (including the last hours of the long interval and the subsequent dialysis session) with increased risk of cardiovascular morbidity and mortality. Previous observational studies support that enhanced-frequency home haemodialysis is associated with reduced risk of all-cause mortality, while randomized studies suggest that short-daily or alternate-day in-centre haemodialysis offer improvements in left ventricular hypertrophy, blood pressure, phosphorous homeostasis and other intermediate end points when compared with conventional thrice-weekly in-centre haemodialysis. This article summarizes available evidence relating long inter-dialytic intervals with elevated cardiovascular risk, potential mechanisms for this association and the main benefits of more frequent dialytic modalities.