Open, decentralized, adaptive cyber-physical systems (ODA-CPSs) have countless novel structural attributes and functional affordances. Consequently, they pose many design and engineering challenges. This paper identifies and analyzes nine of them. They are: (i) handling aggregative complexity, (ii) establishing static and dynamic compositional synergy, (iii) managing dynamic and evolutionary operation in time, (iv) multi-abstraction-based modeling, (v) system integrity verification and behavior validation, (vi) achieving dynamic scalability towards meta-systems, (vii) transformation of big data, (viii) employing testable surrogate prototyping, and (ix) attaining robust social compliance. These challenges should be addressed already in the course of conceptualization and design of these systems. It is shown that a kind of duality is hiding practically in each of these challenges, which are caused by the concurrence of short term dynamic behavior and long term evolution of ODA-CPSs. Though interrelated, these two aspects still need to be handled separate. In order to response effectively to the above challenges, foundational research and operative research need to produce new transdisciplinary insights and new practical principles, respectively. First, previous efforts in these dimensions are critically evaluated. Then it is circumscribed what new knowledge is needed in order to cope with the considered major challenges. Putting everything together, the paper concludes that the grand challenge is in the lack of a dedicated transdisciplinary design theory that could explain how ODA-CPSs should be ideated and synthesized, and that would allow the development of a comprehensive design methodology and computational support tools. Future research will attempt to propose concrete solutions for the discussed challenges and most probably identify other emerging ones.

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