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The rising of chronic illness and the continuous aging of the global population requires a re-organization of health care systems based on relations and exchange of information to address patient needs in the community. The re-organization of health care systems involves interconnected changes and the development of integrated health care information systems and novel eHealth services. In Crete, the Foundation for Research and Technology-Hellas has developed HYGEIAnet, a Regional Health Information Network (RHIN) to contribute to the re-organization of health care systems and information sharing. We present HYGEIAnet, some of the most critical and novel eHealth services developed and deployed, discuss the impact of an RHIN on health care processes, and explore innovative models and services for health delivery and the coordination of care. We then critically discuss lessons learned regarding the effective management of change to overcome organizational and cultural issues in such large-scale initiatives. The paper concludes with policy and practice recommendations for managing change processes in health care organizations.