Rett syndrome (RS) is a progressive disorder that is predominant in females. It is associated with cortical atrophy, stereotyped hand movements mimicking hand-washing, severe mental deficiency, and cortical and extrapyramidal dysfunction. The cause of RS is unknown; no consistent genetic abnormalities, at either the cellular or mitochondrial levels, have been identified. The diagnosis still depends solely upon clinical evidence. The clinical progression of RS is consistent with an arrested neuronal development that may be due to either impaired cellular differentiation or the lack of appropriate trophic factors. Neuropathological studies have confirmed (1) a generalized brain atrophy involving the cerebrum and cerebellum; (2) a decrease in neuronal cell size and increased cell packing density throughout the brain; (3) a reduction in the number of basal forebrain cholinergic neurons; (4) a reduction in the concentration of melanin-containing neurons in the substantia nigra. Biochemical studies have identified (1) a decrease in cholinergic markers in the neocortex, hippocampus, thalamus and basal ganglia; (2) inconsistent and variable changes in biogenic amine biomarkers in post-mortem tissues and cerebrospinal fluid (CSF); (3) an elevation of beta-endorphin levels in the thalamus and glutamate levels in the CSF; (4) no evidence for mitochondrial dysfunction. These data suggest that there is a primary deficit in cholinergic function that might underlie some of the higher cognitive impairments and extrapyramidal dysfunction. Overall, the clinical, biochemical and neuropathological data suggest that RS is a neurodevelopmental disorder that has its greatest effects upon a limited number of neural systems during the first few years of postnatal life.