Rett syndrome (RTT) is a rare neurodevelopmental disorder usually affecting females. It is associated with intellectual and multiple disabilities leading to a high level of dependency in all aspects of daily living including participation in physical activities. This study explored facilitators and barriers to “uptime” (non-sedentary) activities in Danish girls and women with RTT as perceived by parents and professionals using focus groups. Through thematic analysis, one central theme emerged: a constant balance to do the best thing for the girl or woman. Within the central theme, five subthemes of facilitators and barriers were identified relating to the individual and the physical, organizational, social, and attitudinal environments. Environmental barriers can be reduced through policy and management-level changes in health promotion and strong advocacy of physical activity by health professionals. Targeting both facilitators and barriers of “uptime” activities enables the planning and implementing of health-promoting interventions in individuals with RTT.