Nuclear receptors (NRs) represent a vital class of ligand-activated transcription factors responsible for coordinately regulating the expression of genes involved in numerous biological processes. Transcriptional regulation by NRs is conducted through interactions with multiple coactivator or corepressor complexes that modify the chromatin environment to facilitate or inhibit RNA polymerase II binding and transcription initiation. In recent years, studies have identified specific biological roles for cofactors mediating NR signaling through epigenetic modifications such as acetylation and methylation of histones. Intriguingly, genome-wide analysis of NR and cofactor localization has both confirmed findings from single-gene studies and revealed new insights into the relationships between NRs, cofactors and target genes in determining gene expression. Here, we review recent developments in the understanding of epigenetic regulation by NRs across the genome within the context of the well-established background of cofactor complexes and their roles in histone modification.