The current status of neurobiological and neurochemical research on Rett syndrome is reviewed, and correlations are developed with previously described neurophysiological, neuroimaging, neuropathological, and immunohistochemical changes. We review the abnormalities reported in the biogenic amine neurotransmitters/receptor systems, and of beta-phenylethylamine, an endogenous amine synthesized by the decarboxylation of phenylalanine in dopaminergic neurons of the nigrostriatal system. We also discuss the roles of other neurotransmitters, including beta-endorphin and substance P, and neurotrophic factors, including nerve growth factors. Recently, DNA mutations in the methyl-CpG binding protein 2, mapped to Xq28, have been identified in some patients with Rett syndrome. The multiple abnormalities in the various neurotransmitters/receptor systems explain the pervasive effects of Rett syndrome.