For decades, simulation has been used primarily for facility design improvements. Domains like manufacturing, airports, mining, ports, call centers, supply chains, and military have provided a rich set of case studies describing how simulation has been used to save hundreds of thousands, sometimes even millions, of dollars per project. These are well accepted and documented applications of Discrete Event Simulation (DES). We will first discuss those typical benefits and how those same design-related benefits can be realized in Industry 4.0 applications. But Industry 4.0 introduces many new modeling demands. This chapter also discusses some of those new demands and how mainstream DES technology can be used to help assess the impact of advanced features, identify areas of risk before implementation, evaluate the performance of alternatives, predict performance to custom criteria, standardize data, systems, and processes, establish a knowledgebase, and aid communication. We will illustrate these concepts with four case studies as well as provide a brief tutorial on building a model of such a system using the Simio DES product.