The roles of vitamin D, mediated through its conversion to 1,25-dihydroxyvitamin D(3) (calcitriol), have been expanded recently through new knowledge about the range of tissues capable of activating it and the breadth of the genes under its regulatory control. This basic science together with the fact that numerous studies across North America are revealing that vitamin D insufficiency/deficiency (as defined by 25-OH-D levels <30 ng/ml) is extremely common (>80%) in dialysis patients are indicative that these patients have two vitamin D-related problems that require different treatment regimens. Combinations of vitamin D(3) (cholecalciferol) or vitamin D(2) (ergocalciferol) and an active calcitriol analog should be used to treat their vitamin D deficiency and their calcitriol hormone insufficiency, respectively. This mini-review provides the case for combination therapy.