OBJECTIVES: Rett syndrome, a rare disorder caused by mutations in the X-linked MECP2 gene, occurs almost exclusively in girls and causes severe developmental impairment. We assessed the economic burden of care imposed on patients with Rett syndrome and their families, and clinical trials on therapeutic approaches for Rett syndrome. METHODS: Two systematic literature reviews related to Rett syndrome were performed on 25 June 2018. A search of economic burden in MEDLINE, Embase, Cochrane Library, and Database of Abstracts of Reviews of Effects yielded 133 articles; intervention type and costs were extracted from 9 articles (4 studies). A search of clinical trials in MEDLINE, Embase, ClinicalTrials.gov, and Cochrane Library yielded 652 articles; efficacy/safety were extracted from 28 retrieved articles (20 studies). RESULTS: In the economic burden studies, enteral feeding and assisted walking increased the risk of respiratory-related hospital admissions, while length-of-stay was lower in younger patients. Mean recovery-stay after scoliosis-correcting surgery was 18.2 days and 12.3 days in each of two studies. Care integration improved outcomes and reduced costs. Of 20 clinical studies identified (15 randomized controlled trials, 5 single-arm; N=8–82; follow-up 1–26 months), 19 focused on pharmacological symptom treatment; 1 examined environmental enrichment effects; none targeted the underlying cause. The most common primary endpoints were Rett syndrome Gross Motor Scale, Clinical Severity Score, Motor and Behavioral Assessment, and the Anxiety Depression and Mood Scale. Naltrexone, trofinetide, and mecasermin demonstrated clinical benefits versus placebo, but most treatments yielded no significant improvement. Clinical practice guidelines and treatment patterns data were limited. CONCLUSIONS: There are little data on costs of managing patients with Rett syndrome. Because the only available therapies manage symptoms, there is demand for safe and effective treatments targeting the underlying cause, such as gene therapy, which could improve quality of life and prognosis for patients with Rett syndrome.