Rett syndrome (RS) is a neurological disorder that mainly, and possibly exclusively, affects girls. After its description in 1966 by Andreas Rett in the Wiener Klinische Wochenschrift, awareness and interest in RS were enhanced by the 1983 report of Hagberg et al. in the Annals of Neurology. Diagnosis, and indeed the hypothesis that it exists, continue to be based upon a consistent constellation of clinical features observed in thousands of female patients world-wide. A diagnostic marker has not been identified. Notwithstanding this serious limitation, it is generally agreed that RS is a distinct entity and that it is genetically determined. Although it is associated with devastating loss of function between infancy and the fifth year of life, its course becomes relatively static thereafter, setting it apart from most of the genetic neurodegenerative disorders of childhood. Neuropathological and neurochemical studies call attention to RS as a neurodevelopmental disorder. Clarification of its pathogenesis may provide new insight into normal brain development. This report summarizes existing information and concepts about RS, and presents recent advances.