Cytosine residues in the sequence 5＇CpG (cytosine-guanine) are often postsynthetically methylated in animal genomes. CpG methylation is involved in long-term silencing of certain genes during mammalian development(1,2) and in repression of viral genomes(3,4). The methyl-CpG-binding proteins MeCP1 (ref. 5) and MeCP2 (ref. 6) interact specifically with methylated DNA and mediate transcriptional repression(7-9). Here we study the mechanism of repression by MeCP2, an abundant nuclear protein that is essential for mouse embryogenesis(10). MeCP2 binds tightly to chromosomes in a methylation-dependent manner(11,12). It contains a transcriptional-repression domain (TRD) that canfunction at a distance in vitro and in vivo(9). We show that a region of MeCP2 that localizes with the TRD associates with a corepressor complex containing the transcriptional repressor mSin3A and histone deacetylases(13-19). Transcriptional repression in vivo is relieved by the deacetylase inhibitor trichostatin A(20), indicating that deacetylation of histones (and/or of other proteins) is an essential component of this repression mechanism. The data suggest that two global mechanisms of gene regulation, DNA methylation and histone deacetylation, can be linked by MeCP2.