A smart city represents an improvement of today’s cities, both functionally and structurally, that strategically utilizes several smart factors, capitalizing on Information and Communications Technology (ICT) to increase the city’s sustainable growth and strengthen the city’s functions, while ensuring the citizens’ enhanced quality of life and health. Cities can be viewed as a microcosm of interconnected “objects” with which citizens interact daily, which represents an extremely interesting example of a cyber physical system (CPS), where the continuous monitoring of a city’s status occurs through sensors and processors applied within the real-world infrastructure. Each object in a city can be both the collector and distributor of information regarding mobility, energy consumption, air pollution as well as potentially offering cultural and tourist information. As a consequence, the cyber and real worlds are strongly linked and interdependent in a smart city. New services can be deployed when needed, and evaluation mechanisms can be set up to assess the health and success of a smart city. In particular, the objectives of creating ICT-enabled smart city environments target (but are not limited to) improved city services; optimized decision-making; the creation of smart urban infrastructures; the orchestration of cyber and physical resources; addressing challenging urban issues, such as environmental pollution, transportation management, energy usage and public health; the optimization of the use and benefits of next generation (5G and beyond) communication; the capitalization of social networks and their analysis; support for tactile internet applications; and the inspiration of urban citizens to improve their quality of life. However, the large scale deployment of cyber-physical-social systems faces a series of challenges and issues (e.g., energy efficiency requirements, architecture, protocol stack design, implementation, and security), which requires more smart sensing and computing methods as well as advanced networking and communications technologies to provide more pervasive cyber-physical-social services. In this paper, we discuss the challenges, the state-of-the-art, and the solutions to a set of currently unresolved key questions related to CPSs and smart cities.