The vitamin D receptor (VDR) binds the active form of vitamin D (1,25-dihydroxyvitamin D3). It belongs to the family of trans-acting transcriptional regulatory factors and shows sequence similarity to the steroid and thyroid hormone receptors. The gene was cloned by Baker and colleagues in 1988 and maps to chromosome 12q13.11 [1]. It consists of nine exons with at least six isoforms of exon 1, spans 63.5 kb, and encodes a 427 amino acid protein [2]. Alternative splicing results in multiple transcript variants encoding the VDR protein of different lengths [3,4]. The interaction of 1,25-dihydroxyvitamin D3 with VDR modulates many biological activities of the neural, immune, and endocrine systems, including calcium and phosphorous homeostasis, apoptosis, and cell differentiation (reviewed by Hewison and colleagues [5-7]). Its pleiotropic property is reflected by the findings that VDR is expressed in at least 37 tissues, which can roughly be grouped into seven biological systems (calcium homeostasis, immune, pancreatic β cells, muscle, cardiovascular, brain, and lung) [8-10]. The most characterized mechanism is the binding of vitamin D3 to nuclear VDR, which activates the receptor to form a heterodimer with the retinoid-X receptor and interacts with a specific DNA sequence on the gene promoter regions called the ‘vitamin D response element’ (VDRE). Transcription repressors occupying the VDRE are then replaced by transcription activators to initiate transcription of targeted genes. Microarray analyses using different human cell lines have identified over 100 genes with VDREs in the promoter regions, all potential targets of the 1,25-dihydroxyvitamin D3–VDR complex [11-13]. In human oral squamous carcinoma SCC25 cells, genes with characterized VDREs and of which demonstrated greater than 10-fold increase after treatment with 1,25-dihydroxy-vitamin D3 include 24-hydroxylase (CYP24), 17β-hydroxy-steroid dehydrogenase (HSD17B2), CD14 (CD14), type XIII collagen (COL13A1), and 5-lipoxygenase (ALOX5) [13]. The effect of 1,25-dihydroxyvitamin D3 by binding to VDR in the nucleus is often described as the slow-acting genomic effect; the effect will take days or hours to be noticed. Alternatively, 1,25-dihydroxyvitamin D3 can bind to VDR located in the caveolae in the plasma membrane to exert rapid responses through production of second messengers [14]. Pathways that have been shown to be activated by the 1,25-dihydroxyvitamin D3–VDR[memb] complex include mitogen-activated protein kinase-dependent [15], cAMP-dependent [16], phospholipase A2-dependent [17], phospholipase C-dependent [18], phosphatidylinositol 3-kinase-dependent [19], and protein kinase C-dependent [20] pathways. Examples of such rapid response include rapid Ca2+ absorption in the duodenum [21,22], opening of Cl− channels and secretion in osteoblasts, insulin secretion from pancreatic β-cells [23,24], and vascular smooth muscle cell migration [19].