The recent identification of mutations in the gene, MECP2, in girls with Rett syndrome (RS) firmly establishes the molecular genetic basis of this X-linked dominant disorder. This discovery, with ramifications far beyond establishing the gene for RS, represents a dramatic conclusion to an intensive, decade-long search. MECP2 encodes a methyl-CpG-binding protein (MeCP2) involved in transcriptional silencing of a yet to be defined number and type of genes. The clinical spectrum of resultant disorders extends well beyond RS. Indeed, the clinical phenotypes for MECP2 mutations range from mild disability in the mother of a girl with RS to rapidly progressive encephalopathy in her brother. Further, the recent identification of MECP2 mutations in boys with phenotypes quite different from RS adds yet another element to the mix. Within the classic RS group, clinical severity varies remarkably, depending at least in part on the degree of non-random X-inactivation. Those with clinical patterns in the border zones of RS remain to be examined fully for less severe mutational events. Further, the pathobiology of RS and the role of transcriptional silencing as a disease-producing mechanism could be a prototype for other disorders of neurodevelopment. Thus, the identification of mutations in MECP2 creates completely new vistas as to fundamental neurobiologic processes, to disease mechanisms in the neurodevelopmental disabilities, and to potential new therapeutic strategies for RS and related disorders. Copyright © 2001 Elsevier Science B.V.