Rett syndrome is a neurodevelopmental disorder caused by mutations in Mecp2. Here the authors show that Mecp2 loss-of-function leads to upregulation of the NF-κB pathway, and that reducing NF-κB signalling ameliorates phenotypes of Mecp2-null mice, thus offering a potential therapeutic strategy. Here, NFKB1 is linked to atypical Rett syndrome.