This handbook brings together diverse domains and technical competences of Model Based Systems Engineering (MBSE) into a single, comprehensive publication. It is intended for researchers, practitioners, and students/educators who require a wide-ranging and authoritative reference on MBSE with a multidisciplinary, global perspective. It is also meant for those who want to develop a sound understanding of the practice of systems engineering and MBSE, and/or who wish to teach both introductory and advanced graduate courses in systems engineering. It is specifically focused on individuals who want to understand what MBSE is, the deficiencies in current practice that MBSE overcomes, where and how it has been successfully applied, its benefits and payoffs, and how it is being deployed in different industries and across multiple applications. MBSE engineering practitioners and educators with expertise in different domains have contributed chapters that address various uses of MBSE and related technologies such as simulation and digital twin in the systems lifecycle. The introductory chapter reviews the current state of practice, discusses the genesis of MBSE and makes the business case. Subsequent chapters present the role of ontologies and meta-models in capturing system interdependencies, reasoning about system behavior with design and operational constraints; the use of formal modeling in system (model) verification and validation; ontology-enabled integration of systems and system-of-systems; digital twin-enabled model-based testing; system model design synthesis; model-based tradespace exploration; design for reuse; human-system integration; and role of simulation and Internet-of-Things (IoT) within MBSE.