The contribution proposes innovative methods for design and ergonomic configuration of tools, equipment and manual workplaces for automobile assembly tasks, in order to increase the worker’s welfare and the system’s performance by improving general safety conditions. Developed activities are part of the research project “DEWO – Design Environment for WorkPlace Optimization”, financed by Italian Government to the Second University of Naples. The aim of this project is to identify new methods for optimization of assembly tasks in a virtual environment in terms of overall integration among materials management, working tasks organization and layout, starting from the principles of "WorkPlace Organization" and the modern theories of "Lean Production ". The manufacturing industry is heading to the ever more pushed use of digital technologies in order to achieve very dynamic production environments and to be able to develop continuous process and product innovations to fit into the so called Fourth Industrial Revolution, Industry 4.0. The main goal of Industry 4.0 is to “rethink” companies through the use of digital, to reconsider the design approach and to monitor the production process in real time. The research addresses the evolution of innovation 4.0 in relation to the discipline of design, where the management of knowledge in the production process has led to the strengthening and improvement of tangible goods. Starting by current ergonomic analysis models and innovative approaches to the process of industrial production line, the manufacturing processes in the virtual environment were defined and optimized with the use of innovative 3D enjoyment technologies. The constant interaction among the different disciplines of design, engineering and occupational medicine, enables the creation of advanced systems for simulating production processes based on virtual reality and augmented reality, mainly focused on the needs and requirements of the workers on a production line where it is possible to bring out the interaction between real and virtual factory (Cyber-Physical System). The objective is to define new models of analysis, of development and testing for the configuration of ergonomic processes that improve and facilitate the human-machine interaction in a holistic view, in order to protect and enhance human capital, transferring the experiences and knowledge in the factory system, key factors for the company and for the sustainability of workers welfare levels.DOI: http://dx.doi.org/10.4995/IFDP.2016.3297