Mutations in the MECP2 gene that encodes a transcription regulator known to affect a myriad of biological functions are the cause of RTT. Our pioneer work in RTT contributed to the definition of genotype-phenotype correlations in Humans and highlighted behavior and pathological alterations early in the development of a mouse model (Mecp2 knock out). We have identified subtle, but critical alterations in the early postnatal development of neurological reflexes, an early indicator of future neurological disorder (Genes Brain Behav 6: 277-286 [2007]). In a second study, the aim was to determine the role that different brain regions and neurotransmitters play in the origin and development of RTT. Here, we found that deregulation of norepinephrine and serotonin systems, in brain regions that participate in motor control, are involved in the pathophysiology of RTT and I highlighted the contribution of cortical regions from the early stages of the disease, concurrent with the reported involvement of brainstem regions (Neurosci 170: 453-67 [2010]). Presently, we seek to identify new molecular players underlying neuronal architecture changes and intellectual disability in RTT to identify novel therapeutic targets to alleviate the symptoms of this severe pathology.