Here, we will provide an overview of recent advances in understanding the underlying mechanism of disease in RTT and the associated genetic mutations in the MECP2 gene along with the pathobiology of the disease, the role of the two most studied protein variants (MeCP2E1 and MeCP2E2 isoforms), and the regulatory mechanisms that control MeCP2 homeostasis network in the brain, including BDNF and miR132. The gene discussed is BDNF; the disease is Rett syndrome.