Human in the factory is one of the main themes of the Factory of the Future, in this context the aim of this paper is to present the new issues for workers safety and the integrated design concepts or methodologies which have to be taking into account. New paradigms come into being: the uncertainty of the demand in terms of products as well as production rate, product customization, integration product / service, the manufacturing processes are not fixed, so the manufacturing times cannot be foreseen, reconfiguration of machine tools as manufacturing systems, space organization, autoorganization, planning …, new technologies are implemented: robots, plug and play devices, virtual / augmented reality, sensors, OPC standards, connected objects,… Several tasks are performed by the workers, the robots or in collaboration. The workers are place in the center of the Factory of the future but this concept introduce hazard events, problems of health and safety (physical or cognitive tasks, fatigue, stress, space or time organization, interfaces Human-robot, to take into account of the different life situations…). So the aim of the paper is to present studies carrying out in order to propose to the machine or manufacturing systems designers as well as production managers structured methods, models, tools in order to get safe working situations in the frame of the factory of the future paradigm.