Industry 4.0 (also known as the Fourth Industrial Revolution) is a reality. Railroads, including their partners in the transportation supply chain, are at the beginning of their journey to establishing true end-to-end digital continuity. For example: Industrial Internet of Things (IIoT); Positive Train Control (PTC) and Enhanced Train Control (ETC); and AI (artificial intelligence)-based automation such as expanding autonomous inspection to include predictive analytics for track data. How do we know that these solutions and systems are safe and that there are no lurking issues? How do we know that the integration of multiple components from vendors, partners, and even from within meet safety objectives? How do we know if safety integrity is preserved after a change is made? How do we shift the paradigm where safety moves from a cost center to a value-added business driver? In Part 2 of this three-part series, which accompanies an article in Railway Age’s November 2020 issue, Sonia Bot, The BOT Consulting Group Inc., and Tony Zenga, CMTIGroup Inc., make the case for system safety as the necessary discipline for railroads to embed as they move forward in innovating and advancing in the 21st century.