Synaptic communication is a highly regulated process of contact between cells allowing information to be stored and modified. Synaptic formation and maturation is the result of interactions between molecular factors and the external environment to establish communication in the brain. One disorder associated with faulty synapse communication is Rett syndrome (RTT). RTT is the leading form of severe intellectual disability in females, affecting approximately 1:10,000 females worldwide, without predisposition to any particular racial or ethnic group. Mutations in MECP2, the gene encoding methyl-CpG-binding protein-2, have been identified in more than 95% of individuals with RTT. Birth and the milestones of early development appear to be normal in individuals with RTT until approximately 6-18 months, when in the subsequent months and years that follow, physical, motor and social-cognitive development enters a period of regression. The clinical management of these individuals is extremely multifaceted, relying on collaborations of specialists and researchers from many different fields. In this critical literature review, an overview of RTT is provided, with a therapeutic summary of clinical trials in RTT and preclinical studies using mouse and cell models of RTT. © 2013 Future Medicine Ltd.