OBJECTIVE Vitamin D has diverse biological actions, and consequently the mechanisms behind how it regulates gene transcription are diverse. Unlike its well described positive effects on gene transcription, little is known about how vitamin D induces transcriptional repression. RESULTS Vitamin D-induced transcriptional repression of several negative vitamin D receptor target genes has been studied on a molecular level. A new class of negative vitamin D response elements, which are E-box-type motifs, bind the bHLH-type transcriptional activator (VDIR) together with a histone acetyltransferase coactivator. The vitamin D receptor, activated by vitamin D, does not directly bind to the negative vitamin D response elements, but instead associates with VDIR. This leads to the dissociation of the histone acetyltransferase coactivator and recruitment of a histone deacetylase corepressor to transrepress transcription of the target gene promoter. CONCLUSIONS Histone inactivation induced by histone deacetylase co-repressors appears to facilitate vitamin D-induced transcriptional repression via the vitamin D receptor. Following vitamin D binding, structural alteration of the DNA-unbound vitamin D receptor triggers transcriptional repression. Given this, the mechanisms behind vitamin D-induced transcriptional repression are probably more complex than those of vitamin D-induced transactivation.