It has been almost 40 years since the cloning of the cDNA encoding the vitamin D receptor, which confirmed its membership in the nuclear receptor family of ligand-regulated transcription factors. Since that time, we have learned a tremendous amount about its structure and mechanisms of action. The VDR heterodimerizes with RXRs to form so-called non-permissive heterodimers. Unlike that of related TR/RXR and RAR/RXR heterodimers, VDR/RXR DNA binding is strongly ligand dependent, and, reciprocally, DNA binding allosterically alters the structure of the VDR ligand binding domain. Studies from numerous laboratories have shown that, like other nuclear receptors, the agonist-bound VDR recruits a bewildering array of cofactors necessary for transactivation. While many are recruited to modify the structure of chromatin, there is growing evidence that the agonist-bound VDR also recruits the proteasome and that proteasomal degradation is required for optimal transactivation. The field has also developed a vast array of synthetic VDR ligands. Mechanisms of agonism, superagonism and antagonism will be discussed.