Fat-soluble ligands like vitamin A/D and steroid hormones activate their cognate nuclear receptors for ligand-dependent transcriptional regulation. Nuclear receptors constitute a gene superfamily with 48 members in higher mammals, and act as ligand-dependent transcription factors to bind stably to specific DNA elements in ligand/NR target gene promoters. Hence, most of biological actions of fat-soluble ligands are generally thought to mediate NR-mediated gene regulation. Starting in early 1990, transcriptional co-regulators supporting ligand-dependent transcriptional controls by NRs have been characterized. Initially, the transcriptional co-regulators were believed to couple with histone acethylation/deacethylation, and thereby histone acethyltransferases (HATs) and histone deacethylases (HDACs) were characterized as NR co-activators and co-repressor, respectively. However, recent progress in chromatin biology and epigenome have revealed that other histone modifying enzymes and chromatin remodelers are potential co-regulators for NRs. In this review, these cuttingedge aspects are discussed together with our recent findings on NR co-regulators.