Objective: The object of the present study is to advance our understanding of the cognitive profile of Rett syndrome (RTT), an X-linked neurodevelopmental disorder caused by mutations in the MECP2 gene. We focus on sustained attention, which plays a critical role in driving cognitive growth, and use an innovative, gaze-based task that minimizes demands on the limited verbal and motor abilities associated with RTT. Method: The task required the ability to sustain attention on a visual target (a butterfly) while inhibiting a prepotent response to look to moving distractors (trees and clouds) presented in the peripheral visual field. The sample included children with RTT (N = 32) and their typically developing (TD) counterparts (N = 32), aged 2–12 years. Results: Our findings revealed that children with RTT had more difficulty sustaining attention (with the TD group averaging 60% looking at the butterfly vs. only 25% for the RTT group). Furthermore, RTT was associated with difficulties in 3 fundamental factors influencing sustained attention: engagement, distractibility, and reengagement. The RTT group was slower to engage, more distractible, and slower to reengage. Conclusion: Our findings identify a fundamental disruption to sustained attention in RTT, determine factors related to this impairment, and pinpoint cognitive areas that could serve as markers for evaluating the effectiveness of pharmacological and behavioral interventions.