This article provides a comprehensive and in-depth overview of our work on knowledge discovery in simulations. Application-wise, we focus on manufacturing simulations. Specifically, we propose and discuss a methodology for designing, executing, and analyzing large-scale simulation experiments with a broad coverage of possible system behavior targeted at generating knowledge about the system. Based on the concept of data farming, we suggest a two-phase process which starts with a data generation phase, in which a smart experiment design is used to set up and efficiently execute a large number of simulation experiments. In the second phase, the knowledge discovery phase, data mining and visually aided analysis methods are applied on the gathered simulation input and output data. This article gives insights into this knowledge discovery phase by discussing different machine learning approaches and their suitability for different manufacturing simulation problems. With this, we provide guidelines on how to conduct knowledge discovery studies within the manufacturing simulation context. We also introduce different case studies, both academic and applied, and use them to validate our methodology.