Rett syndrome (RTT) is a severe developmental-neurological disorder characterized by profound and progressive loss of intellectual functioning. Mutations in the methyl-CpG-binding protein 2 gene (MECP2) are present in the majority of cases of RTT. The high incidence of sudden death in RTT and the suspect that autonomic nervous system alterations might be the underlaying pathogenetic mechanism have spurred efforts, in the last decade, for the study of the autonomic nervous system in Rett girls. Recently, many studies were performed in mice with Mecp2 mutations to know the pathophysiology of autonomic nervous system alterations observed in RTT. Neurometabolic alterations observed in RTT include reduced levels of dopamine, serotonin, noradrenaline, choline acetyltransferase, nerve growth factor (NGF), substance P, glutamate and other aminoacids and their receptor levels in the brain. Breathing irregularities with various respiratory patterns were described in RTT suggesting autonomic nervous system alterations. In RTT a loss of physiological heart rate variability associated with an increase of adrenergic tone is also observed. Pharmacological manipulation of brainstem neurotransmitters and neurotrophic drugs, as acetyl-L-carnitine, have been suggested in the treatment of autonomic alterations of Rett children. Recently, the principle of reversibility in a mouse model was established, raising the possibility that neurological defects seen in this model and related human disorders are not irrevocable.