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A century of revolutionary growth in aviation has made global travel a reality of daily life. Aircraft and air transport overcame a number of formidable challenges and hostilities in the physical world. Success in this arduous pursuit was not without leveraging advances of the "cyber" layer, i.e., digital computing, data storage and networking, and software, in hardware, infrastructures, humans, and processes, within the airframe, in space, and on the ground. The physical world, however, is evolving continuously in the 21st century, contributing traffic growth and diversity, fossil fuel and ozone layer depletion, demographics and economy dynamics, as some major factors in aviation performance equations. In the next 100 years, apart from breakthrough physical advances, such as aircraft structural and electrical designs, we envision aviation's progress will depend on conquering cyberspace challenges and adversities, while safely and securely transitioning cyber benefits to the physical world. A tight integration of cyberspace with the physical world streamlines this vision. This paper proposes a novel cyber-physical system (CPS) framework to understand the cyber layer and cyber-physical interactions in aviation, study their impacts, and identify valuable research directions. This paper presents CPS challenges and solutions for aircraft, aviation users, airports, and air traffic management.