The vitamin D endocrine systems plays a critical role in calcium and phosphate homeostasis. The active form of vitamin D, 1, 25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)], binds with high affinity to a specific cellular receptor that acts as a ligand-activated transcription factor. The activated vitamin D receptor (VDR) dimerizes with another nuclear receptor, the retinoid X receptor (RXR), and the heterodimer binds to specific DNA motifs (vitamin D response elements, VDREs) in the promoter region of target genes. This heterodimer recruits nuclear coactivators and components of the transcriptional preinitiation complex to alter the rate of gene transcription. 1,25(OH)(2)D(3) also binds to a cell-surface receptor that mediates the activation of second messenger pathways, some of which may modulate the activity of the VDR. Recent studies with VDR-ablated mice confirm that the most critical role of 1, 25(OH)(2)D(3) is the activation of genes that control intestinal calcium transport. However, 1,25(OH)(2)D(3) can control the expression of many genes involved in a plethora of biological actions. Many of these nonclassic responses have suggested a number of therapeutic applications for 1,25(OH)(2)D(3) and its analogs.