In patients with chronic kidney disease (CKD) and end-stage renal disease (ESRD), 25OH-vitamin D (calcidiol) deficiency or insufficiency is a common finding with high prevalence. Numerous epidemiological studies have found an independent association of low levels of calcidiol with increased morbidity and mortality. Within different patient cohorts, application of cholecalciferol or ergocalciferol (native vitamin D) as well as calcifediol can help replenish vitamin D levels in patients with and without renal disease. However, it is unclear if such an approach is effective in modifying relevant clinical end-points. Currently available data are insufficient to clearly define situations in which calcifediol therapy might be superior to ergocalciferol or cholecalciferol therapy in terms of increasing calcidiol levels in CKD / ESRD. Similar to ergocalciferol or cholecalciferol application, also calcifediol therapy needs to undergo testing in randomized, controlled trials (RCT) in severe CKD or ESRD with reasonable end-points before recommendations about therapy can be established.