Smart factories must speed up their processes to face new manufacturing challenges and, at the same time, demonstrate an extremely high degree of flexibility to reduce production costs and time. This kind of issues can be addressed by the cooperation between humans and robots in a mixed human-robot working environment. Robots have the compelling advantage of spatial precision and repeatability as well as the capability of applying defined forces. Humans, on the other hand, are especially skilled at complex manipulations and adapting to changing task requirements. In this complicate scenario of co-shared workplace and continuous human-robot interaction, safety strategies are a key requirement to avoid possible injuries to humans or fatal accidents. This chapter proposes a systemic approach to respond to these requirements. The approach merges and manages multiple sensing sources, redundant transmission protocols and software decision mechanisms, aiming to guarantee a continuous and reconfigurable co-share scenario that enables an operative interaction between human workers and robots in a controlled and safe environment. Furthermore, new technological solutions and innovative methodologies are presented for the definition of a safer workplace in human-robot interaction scenarios.