Rett syndrome is caused by mutations in the gene that encodes methyl-CpG-binding protein 2 (MECP2). Previous studies have shown that many disease-causing mutations are clustered in its DNA-binding region. Bird and colleagues have identified another cluster of Rett syndrome-associated mutations in the C-terminal half of MECP2. These mutations disrupt the interaction between MECP2 and NCOR–SMRT co-repressor complexes, impairing transcriptional repression. Importantly, mice expressing one of these MECP2 mutations exhibited severe Rett-like phenotypes, indicating that a core function of MECP2 is to recruit co-repressors to DNA.