Methylation of DNA at CpG dinucleotides represses gene transcription. Methylation plays an important role in development, imprinting, X-chromosome inactivation and tissue-specific gene expression, but the mechanisms of methylation-induced repression are still unclear. In the December Molecular and Cellular Biology, Schubeler et al. show that localized histone deacetylation can explain methylation-induced repression (Mol Cell Biol 2000, 20:9103-9112). The authors used an elegant technique called recombinase-mediated cassette exchange (RMCE) to introduce in vitro-methylated DNA at defined chromosomal positions. They used the Cre recombinase to insert methylated or unmethylated forms of the human β-globin gene promoter driving a green fluorescent protein (GFP) reporter gene. Methylation repressed GFP expression, and was stable in cells over at least 12 weeks in culture. Methylation did not affect DNA replication or global chromatin remodeling. However, methylation caused a hypoacetylation of histones H3 and H4 within the transgene. These observations support a model in which methylated DNA represses local transcription by recruiting histone deacetylase activity.