Transcription factors require coactivators and corepressors to modulate transcription in mammalian cells. The vitamin D receptor (VDR) utilizes coactivators and corepressors to gain tight control over the activity of a diverse set of genes that can regulate calcium transport, slow proliferation and promote immune responses. We have recently established the VDR/RXR cistrome in human colon cancer cells and have linked these binding sites to the genes that are regulated by 1α,25-dihydroxyvitamin D₃ (1,25(OH)₂D₃). In additional studies described herein, we demonstrate that the coactivators SRC1, CBP and MED1 are recruited to upregulated genes to facilitate transcription as expected. SRC1 was the most highly correlated to VDR/RXR binding (50%). However, we also found that corepressor molecules such as NCoR and SMRT were present along with SRC1, CBP or MED1 at these 1,25(OH)₂D₃ activated gene enhancers. Interestingly, genome-wide NCoR binding mimicked VDR binding by increasing its association with VDR binding in response to 1,25(OH)₂D₃ treatment. Overall, these data indicate a complex role for corepressor and coactivator complexes in the activation or active repression of 1,25(OH)₂D₃ responsive genes. This article is part of a Special Issue entitled ‘Vitamin D Workshop’.