Care pathways (CPW) are used worldwide to structure care processes within the patient-centered care concept. Rare diseases (RD), defined as those affecting less than 5 persons per 10,000 and including up to 10,000 different diseases, present unique challenges to CPW development due to their rarity and a large number of disease entities, chronic and frequently disabling nature, heterogeneous manifestation, multisystem involvement, and complexity in diagnostics and treatment. However, failure to develop RD CPWs eventually leads to long diagnostic odysseys, limited and unequal access to RD treatments, and a huge burden of complex care coordination that lies on the shoulders of patients and their families, imposing many personal, professional and social life difficulties, and diminishing their quality of life. In the development of RD CPW, there is a need to ensure smooth horizontal and vertical care integration, multiple transitions, and long-term care coordination across many geographically distant care providers and to find a fine balance between centralized expertise-based, complex, highly specialized services and possibilities for local care provision, patient empowerment and self-management, and digital healthcare. Established in 2017, European Reference Networks may have a high added value through an increase in accessibility and quality of services, economies of scale, scope and speed in the development of lacking evidence-based, educational and other resources for RD CPW, and speeding up innovation development and translation into RD CPW. However, their full benefits may only be reaped through a pan-European collaboration, universal acceptance of common European values and open-mindedness for sometimes disruptive innovation in the provision of healthcare across all Member States of the European Union.