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Vitamin D3 is made in the skin and modified in the liver and kidney to form the active metabolite, 1,25-dihydroxyvitamin D3 (calcitriol). Calcitriol binds to a nuclear receptor, the vitamin D receptor (VDR), and activates VDR to recruit cofactors to form a transcriptional complex that binds to vitamin D response elements in the promoter region of target genes. During the past three decades the field has focused mainly on the role of VDR in the regulation of parathyroid hormone, intestinal calcium/phosphate absorption and bone metabolism; several VDR agonists (VDRAs) have been developed for the treatment of osteoporosis, psoriasis and hyperparathyroidism secondary to chronic kidney disease (CKD). Emerging evidence suggests that VDR plays important roles in modulating cardiovascular, immunological, metabolic and other functions. For example, data from epidemiological, preclinical and clinical studies have shown that vitamin D and/or 25(OH)D deficiency is associated with increased risk for cardiovascular disease (CVD). However, VDRA therapy seems more effective than native vitamin D supplementation in modulating CVD risk factors. In CKD, where decreasing VDR activation persists over the course of the disease and a majority of the patients die of CVD, VDRA therapy was found to provide a survival benefit in both pre-dialysis and dialysis CKD patients. Although VDR plays an important role in regulating cardiovascular function and VDRAs may be potentially useful for treating CVD, at present no VDRA is approved for CVD, and also no serum markers, beside parathyroid hormone in CKD, exist to indicate the efficacy of VDRA in CVD.