Rett Syndrome (RTT) is an X chromosome-linked neurodevelopmental disorder caused by inactivating mutations in the transcription regulator methyl CpG-binding protein 2 (MeCP2). Multiple studies have independently explored the therapeutic potential of adeno-associated viral (AAV) vector-mediated MECP2 gene transfer in mouse models of RTT. Historically, the primary risk anticipated for viral vector-mediated MECP2 gene transfer in vivo has been toxicity caused by supraphysiological expression of exogenous MeCP2. Despite the anticipated risk, early studies examining AAV/MECP2 in vivo have, as a whole, supported a generally optimistic assessment of MECP2 gene therapy. More recently, toxicity assessments have identified dose-dependent side effects of AAV9/MECP2 delivered directly to the cerebrospinal fluid (CSF). Ultimately, accurate monitoring and reporting of these side effects will help ensure the development of safe AAV/MECP2 treatment paradigms as researchers explore strategies to improve widespread but properly regulated MECP2 gene transfer in the central nervous system (CNS). Importantly, despite some variability in apparent safety and efficacy, all MECP2 gene therapy studies have been united by a single feat: published treatment paradigms have extended the survival of RTT mice, regardless of injection route, treatment age, or viral genome design. With the possibility of a translatable gene therapy treatment for RTT emerging, a comprehensive overview of the preclinical MECP2 gene therapy studies published thus far is warranted. This review highlights the main findings of these publications and discusses future directions.