Smart cyber-physical systems (S-CPSs) are complex engineered systems empowered by cyber-physical computing and equipped with the capability of reasoning, learning, adapting, and evolving. As an outcome of data-driven dynamic computing, reasoning capabilities, and the run-time obtained own knowledge, nonlinear and emergent behavior of S-CPSs whilst in operation is an open issue, not experienced in the case of conventional technical systems. This paper analyzes the technical issues of run-time operation and emergent behavior of S-CPSs, reviews the current understanding and state of advancement in designing S-CPSs for run-time, explores the paradox, and issues of designing for runtime adaptation, and synthesizes some general principles that can be taken into consideration when addressing the challenges, first of all, in the context of advanced manufacturing systems. This paper introduces four levels of CPSs according to reasoning capabilities and adaptation freedom of systems, and recognizes the paradox that a system with a higher level of freedom requires a higher level of self-control and resource management according to the overall objective of operation. Specific and common design principles are presented and critically assessed for each advancement level of CPSs. The principles synthesized by the authors provide only a partial fulfillment of the generic need. The planned future research addresses these issues and proposes (largely implementation and application independent) genuine principles for system developers.