Rett Syndrome (RTT) is a severe neurological disorder caused by mutations in the MECP2 gene. This disorder primarily affects brain development, leading to profound cognitive and motor impairments. Conventionally, research on RTT has concentrated on the neurological impact of MECP2 mutations. However, other evidence suggests that the influence of RTT extends beyond neural boundaries, impacting a broad spectrum of other tissues and organ systems. This chapter provides an overview of identified abnormalities in respiratory, skeletal, cardiac, liver, endocrine, urinary, immune, and gastrointestinal systems in patients with RTT or related disease models. We further explore the potential pathways involved in the brain-body circuit and their impact on the development of RTT. These insights not only enhance our understanding of the multi-system involvement in RTT, but also reveal the necessity for a more comprehensive approach to investigating the systemic courses of neurological disorders.