The next-generation cyber-physical systems (CPSs) will not only be limited to industries but will span across multiple application-areas regarding smart cities and regions. These CPSs will leverage the recent advancements in the areas of cloud computing, Internet of Things and big data to provision citizen-centric applications and services such as smart hybrid energy grids, smart waste management, smart healthcare and smart transportation. Challenges regarding context-awareness, quality of service and quality of experience, mobility management, middleware platforms, service level agreements, trust, and privacy needs to be solved to realize such CPSs. This chapter discusses these challenges in detail and proposes ICICLE – a context-aware IoT-enabled cyber-physical system as a blueprint for next-generation CPSs.