A thrice-weekly schedule dominates hemodialysis practice today. Inherent in such a schedule is a 72-hour interweek break over the weekend. A growing body of evidence suggests that this break may be associated with increased cardiovascular morbidity and mortality. Five recent studies have linked dialysis session timing to higher cardiovascular event rates, and have shed light on possible underlying physiologic mechanisms. We reviewed outcome data linking the “long break” to cardiovascular outcomes, and suggest physiologic rationale for this relationship while identifying knowledge gaps that require further study to inform discussions regarding the application and composition of individualized dialysis prescriptions. Further work is needed to determine the relative importance of electrolyte perturbations and hemodynamic shifts in the relationship between the long break and cardiovascular mortality. The evidence suggests that at least in some at-risk patients, an individualized approach to the dialytic schedule and prescription is warranted.