Synopsis Is Human-Systems Integration (HSI) a necessary component of Systems Engineering (SE) or the opposite (i.e., SE a necessary component of HSI)? It all depends on the perspective! If you are a technology-centered engineer, SE will provide you with methods and tools to develop technological systems, and you will need human factors specialists to develop user interfaces and test usability of the end product. In this perspective, HSI is a necessary component of SE. However, if you are human-centered designer, you will need methods and tools to design and develop systems that integrate human and machine requirements from the very beginning of design to decommissioning of the system of systems at stake. This states the question of what we mean by "system." A system is simply a representation that helps figuring out physical and cognitive functions and structures of both people and machines. In this chapter, several areas related to HSI are covered, including task and activity analysis, cognitive engineering, organization design and management, function allocation, complexity analysis, modeling and human-in-the-loop simulation (HITLS). Contemporary HSI design approaches are supported by virtual HITLS, which involves tangibility issues. A discussion is started on the various kinds of data that should be collected and tangibility indicators to develop appropriate HSI. An aeronautical example is provided to illustrate how HSI should be developed in the design and development of a system of systems. We conclude on the necessary shift from rigid automation to flexible autonomy that prefigures the FlexTech (i.e., technological solutions, associated with organizational setups and human functions, that improve operations' flexibility). The 4 th industrial revolution, that is also called Industry 4.0, results from the growing digitalization of industrial organizations, and more generally our sociotechnical society. Depending on approach and background, several new trends are popping up and developing: automation is leading toward cyber-physical systems; computer science to the Internet of things; computer engineering to cloud computing; and human-computer interaction and artificial intelligence to cognitive computing. The 3 rd industrial revolution was technology-centered, considering human-systems integration as an adaptation of people to machines being developed. After World War 2, Human Factors and Ergonomics (HFE) developed as a discipline attempting to make machines usable by people, either anybody (public use) or experts (mostly in life-critical systems). HFE was initially focused on physical ergonomics, as well as health and safety at work. HFE was handled by physicians until the