Organizational, methodological and technological paradigm changes enable a precise, personalized, predictive, preventive and participative approach to health and social services supported by multiple actors from different domains at diverse level of knowledge and skills. Interoperability has to advance beyond Information and Communication Technologies (ICT) concerns, including the real world business domains and their processes, but also the individual context of all actors involved. The paper introduces and compares personalized health definitions, summarizes requirements and principles for pHealth systems, and considers intelligent interoperability. It addresses knowledge representation and harmonization, decision intelligence, and usability as crucial issues in pHealth. On this basis, a system-theoretical, ontology-based, policy-driven reference architecture model for open and intelligent pHealth ecosystems and its transformation into an appropriate ICT design and implementation is proposed.