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This book explores the synergies among the domains of modeling and simulation (M&S) and systems engineering (SE) and the complex problems identified as grand challenges . The chapters discuss what future developments in M&S and SE are required due to evolving technological paradigms and emerging challenges and explore how M&S and SE can synergistically contribute to each other in order to help address grand challenge problems more effectively under a model-driven and simulation-directed systems engineering (SDSE) framework. The text also examines how SDSE can support emerging system paradigms to cope with the increasing complexity of grand challenge problems. The book takes into account aspects of both first-order and higher-order synergies of theory and methodology in M&S and SE, describing how these are guided by the science of complexity to help explain modern scientific and engineering challenges.