BACKGROUND: In 2017, 24 European Reference Networks (ERNs) have been recognized in order to improve rare diseases' management. However, a lack of practical information persists regarding the most adequate ways to fulfil ERNs' quality criteria. OBJECTIVE: Identify the most efficient strategies to improve ERNs' quality. METHODS: 67 strategies, related to 8 activity domains (Quality Management System, healthcare coordination, clinicians' training, inter-ERNs' members collaborations, clinical data management, ERNs' external collaborations/supports, information provided to patients, and ERNs' financing) were selected from peer-reviewed scientific publications. Their usefulness, feasibility and adequacy was evaluated by 17 ERNs-related clinicians and 10 Belgian health policy makers. RESULTS: Results showed that the most efficient strategies are the participation of quality controls, satisfaction surveys among patients and external physicians, diffusion of information about the hospitals' research activities, specific trainings addressed to clinicians, exchange of medical samples between hospitals, and development of adequate clinical databases. The poor practical feasibility of 7 highly-useful strategies was also highlighted, such as major clinicians' concerns regarding legal/ethical frameworks for the reimbursement of crosscountry care and exchange of patients' data. CONCLUSIONS: This study enabled identification of efficient strategies to improve and validate ERNs' quality, expertise and functioning, as well as weaknesses that should be addressed.