This book introduces a new Model-Based Reliability System Engineering (MBRSE) methodology, including its concept connotation, basic theory and technologies, framework of integrated platform and engineering application cases. Different from traditional Reliability System Engineering (RSE) methods that mainly rely on the management of documents, MBRSE is model centric method, with which the design for hexability (including “reliability, maintainability, testability, supportability, environmental adaptability and safety”) is performed by the revolution of united models in complete R&D fields and the process of closed- loop failure mitigation. This method can integrate all techniques and approaches of reliability engineering into the main process of R&D, and therefore is considered as a generalized hexability design and analysis tool. Furthermore, the future perspectives in the development of MBRSE are also presented through the combination of Digital Twin technology.