The increasingly unpredictable demand is among the major challenges of Industry 4.0, asking manufacturing systems (MS) for a capacity of adaptation that accelerates the decision processes. Decision Support Systems (DSS), and among them Simulation-based DSS, must therefore result from new Enterprise Modeling (EM) frameworks, capable of taking advantage of advances in data integration and processing possibilities. After briefly introducing such a new EM framework, MEMO I4.0, this article shows how to use it to derive scalable, flexible simulation models, so as to improve and monitor the MS processes and finally address this challenge. An example to generate a simulation model for a real case study is presented.