Rett syndrome (RTT) is an X-linked postnatal neurodevelopmental disorder, which is primarily caused by mutations in the gene encoding methyl-CpG binding protein 2 (MeCP2). A number of MeCP2 target genes have been identified, including the neurotrophic factor BDNF; however, the functional relevance of these targets has not been established. In this issue of Neuron, Chang et al. provide the first in vivo evidence for a functional interaction between BDNF and MeCP2.