© 2016 Elsevier Inc. All rights reserved. Rett syndrome (RTT) affects 1:10,000 females, causing psychomotor regression and stereotypical hand movements. In the past half century, many clinical, neurobiological, and genetic aspects of RTT have been clarified, including identification of methyl CpG binding protein 2 gene mutations in most. Although loss of language and hand function and problems with ambulation are core disabilities in the disorder, a host of comorbidities affect girls and women with RTT. A Rett specialist typically works closely with other medical professionals, including therapists, nutritionists, social workers, and medical consultants related to the various systems affected. Most girls have problems that require the help of a neurologist or epileptologist, a gastroenterologist, and an orthopedic surgeon, and many require endocrinology and cardiology consultation. Within the past few years, an explosion in the investigation of disease-specific treatments has occurred, and targeted drugs will soon be available to help girls and women with RTT.