Cyber-Physical Systems (CPS) integrate computation, networking and physical processes to produce products that are autonomous, intelligent, connected and collaborative. Resulting Cyber-Physical Systems of Systems (CPSoS) have unprecedented capabilities but also unprecedented corresponding technological complexity. This paper aims to improve understanding, awareness and methods to deal with the increasing complexity by calling for the establishment of new foundations, knowledge and methodologies. We describe causes and effects of complexity, both in general and specific to CPS, consider the evolution of complexity, and identify limitations of current methodologies and organizations for dealing with future CPS. The lack of a systematic treatment of uncertain complex environments and "composability", i.e., to integrate components of a CPS without negative side effects, represent overarching limitations of existing methodologies. Dealing with future CPSoS requires: (i) increased awareness of complexity, its impact and best practices for how to deal with it, (ii) research to establish new knowledge, methods and tools for CPS engineering, and (iii) research into organizational approaches and processes to adopt new methodologies and permit efficient collaboration within and across large teams of humans supported by increasingly automated computer aided engineering systems.Designs 2018, 2, 40 2 of 16 A CPS is thus characterized by an integration of computing and physical elements, typically including feedback loops, into various networks with both physical and cyber interfaces. We consider human-CPS to be a special (but common) category of CPS where humans are integral elements of the system together with technical parts. Figure 1 illustrates interactions between cyber (C), physical (P) and human (H) elements as well as information and physical interactions between the corresponding components. CPS are developed, produced, used and maintained by teams of people (H) and supporting tools, including computer aided engineering software (C) and hardware-in-the-loop simulation ((C) and (P))). We refer to these (people and tools) as Collaborative Information Processing Systems (CIPS). Finally, both CPS and CIPS act in specific environments. For example, the CPS environment may be a factory in which an automated vehicle operates and the CIPS environment includes related stakeholders such as component suppliers as well as applicable legislation and engineering guidelines/standards.