Individuals with Rett syndrome commonly have mutations in the gene that encodes MECP2, a multidomain nuclear protein that acts as a transcriptional repressor. MECP2 binds to chromatin in vitro (particularly methylated CpG dinucleotides) and forms complexes with chromatin-remodelling proteins, but little is known about the dynamics of its interaction with chromatin in vivo. N. Carolyn Schanen and colleagues (p. 1128) now report that, surprisingly, MECP2 is mobile and associates only transiently with chromatin in mouse fibroblasts. Using FRAP, the authors show that EGFP-tagged MECP2 redistributes rapidly to heterochromatic foci after photobleaching. The authors use a series of MECP2 mutants to show that all three regions of the protein – including the transcriptional repression domain and the interdomain region, as well as the methyl-binding domain – promote its association with chromatin. Notably, Rett-syndrome-associated amino acid substitutions in MECP2 substantially increase its mobility. The authors suggest that the transient association of MECP2 with chromatin might be sufficient for it to attract chromatin-modelling proteins to methylated DNA, but that its dissociation allows competing proteins to bind to the site that it vacates. These results shed light on the maintenance of transcriptional repression, and on its role in the pathogenesis of Rett syndrome.