The current status of neurochemistry research with respect to the Rett syndrome (RS) is reviewed and correlations developed with the previously described neuropathologic changes. Despite reports of abnormalities in intermediary metabolism and the biogenic amine neurotransmitters, follow-up studies have failed to support any consistent abnormality in either area. In general, the levels of membrane lipid constituents in various brain regions have been similar to control values. New information suggests a disturbance in the ganglioside pattern leading to a reduction in GD1a and GT1b gangliosides in cerebrum and cerebellum. The corresponding reduction of these gangliosides in cerebrospinal fluid, if shown to be specific for RS, could represent an important clue in confirming the clinical diagnosis. Evidence of pervasive growth failure is presented and the current status of the role of β-endorphins in RS is described. Considerations regarding future directions for research in RS are presented. These strategies include an approach to the fundamental question, namely, the identification of the primary molecular defect.