Introduction. Distribution of public spending on health depends on a variety of factors, from disease burden and system priorities to organisational aspects and costs. Nowadays, virtually all health care systems face serious sustainability challenges. This is particularly true for rare diseases, where priority setting involves complex and often controversial value-laden choices. Method. The theoretical framework underlying the approach of this work is based upon the State of Health in the EU, a two-year initiative undertaken by the European Commission and developed in cooperation with the Organisation for Economic Co-operation and Development and the European Observatory on Health Systems and Policies. Results. The 2017 report identified five cross-cutting sustainability issues: health promotion and disease prevention, primary care, integrated care, health workforce planning and forecasting, person-centred health data. Implications and recommendations. Rare diseases have been one of the priorities of the Community’s programmes for research and development. The EU has stimulated a series of actions in the field of rare diseases. These project activities could set up the practical cooperation and come up with the knowledge to translate and to work on the identified five key challenges of EU Member States health systems’ sustainability and resilience.