Human Systems Integration (HSI) is a new multidisciplinary approach that combines hard sciences together with human and social sciences to the benefit of engineering problem stating and solving, as well as solutions delivery. It is strongly based on Human Centered Design (HCD) that benefits from cognitive engineering, advanced interaction media, organization design and management, life-critical systems, modeling and simulation, and complexity analysis (Boy, 2013). HCD is associated with systems engineering through systemic representation of Technology, Organizations and People (the TOP Model). System's functions and structures are intimately associated toward improving HSI. A system is composed of physical and cognitive functions and structures. A system is recursively defined as a system of systems, in the same way an agent is an agency of agent. HSI, as a discipline, is a natural evolution of Human Factors and Ergonomics (HFE), extending it to engineering design practices. It is also an evolution of Human-Computer Interaction (HCI) by deepening user interface design to human-centered systems engineering design. Industry 4.0 innovations and developments promote 3D printing and Artificial Intelligence (AI) that facilitate HSI by enabling human-in-the-loop simulations and therefore virtual HCD, but require considering the tangibility concept seriously. If 20 th century's automation led to rigidity of practices, 21 st century's autonomy should lead to flexibility of practices both in engineering design and operations. Automation is typically based on single-agent approaches. Conversely, it becomes crucial to investigate autonomy on TOP-Model-based multi-agent approaches. Finally, developing a human-machine system requires us to consider other drivers such as complexity, maturity, stability and sustainability, which shape the structure-function relationships. This keynote will present a plan for HSI research, education, training and practice.