Emerging evidence suggests that vitamin D plays important roles in modulating cardiovascular, immunological, metabolic and other functions. However, numerous questions remain unanswered about the vitamin D-VDR axis. For example, is vitamin D a vitamin? Is it a hormone? Or is it both vitamin and hormone depending on whether it is the precursor or the active metabolite? Current clinical practices focus on measuring 25(OH)D deficiency in the blood. One important question that needs to be addressed is whether 25(OH)D is a proper marker for gauging VDR activation or not. It is well recognized that 25(OH)D is a precursor of the active form of vitamin D, calcitriol; 25(OH)D itself is not effective in activating VDR. In addition, studies have shown that, beside deficiency in vitamin D or 25(OH)D, many other factors such as disease, aging, gene polymorphism, etc. also impact vitamin D metabolism and VDR activation. Is there a need to develop biomarkers that can measure the deficiency in VDR activation at the molecular level so that the root of the problem can be properly corrected? Although vitamin D and its analogs are potentially useful for preventing and treating various diseases, their usage at this point is still rather limited. It is partially due to the fact that there is no way to distinguish whether the lack of effect of vitamin D and its analogs in clinical studies is due to inadequate activation of VDR or a general lack of efficacy. Biomarkers and assays to determine deficiency in VDR activation will be very useful. Another potential issue is that current on-the-market vitamin D analogs used to treat diseases such as hyperparathyroidism secondary to chronic kidney disease, psoriasis and osteoporosis have narrow therapeutic index and considerable side effects. New vitamin D analogs that have a wider therapeutic index without the hypercalcemic liability will allow the expanded usage of this class of drugs into new indications. As the field continues to evolve and new technology advances, the potential of vitamin D and its analogs for the prevention and treatment of various disorders will likely be realized in the near future.