Nuclear hormone receptor mediated transcription has become a paradigm for the study of how gene activation and gene repression are regulated (for review see Mangelsdorf et al. 1995; Tenbaum and Baniahmad 1997). The focus of this review is to highlight recent work from several groups that addresses the mechanisms by which nuclear hormone receptors can function as transcription repressors. Many studies over the past several years have established that nuclear receptors activate gene expression in response to ligand binding and repress gene expression in its absence (for reviews see Shibata et al. 1997; Torchia et al. 1998; Xu et al. 1999). In the presence of ligand, a series of molecular interactions occur resulting in the recruitment of a multiprotein complex that includes the coactivators CBP/p300, pCAF, and p160 proteins (SRC-1, GRIP1/TIF2, ACTR/RAC3/pCIP) (see reviews by Minucci and Pelicci 1999; Xu et al. 1999; Torchia et al. 1998). As these proteins all have intrinsic histone acetyltransferase (HAT) activity (Ogryzko et al. 1996; Spencer et al. 1997; Bannister and Kouzarides 1996), a hallmark of igand-induced transcriptional activation by nuclear hormone receptors is the ability of this complex to alter the local chromatin structure through histone acetylation. Indeed, recent studies demonstrate that estrogen receptor (ER) and retinoic acid receptor (RAR) target gene promoters undergo histone hyperacetylation in response to ligand and that the HAT activity of CBP/p300 protein is required (Chen et al. 1999).