Facility layout design (FLD) is becoming more challenging than ever as manufacturing moves from a traditional emphasis on mass production to an emphasis on mass customization, which requires increased flexibility and adaptability. Of the software tools that support FLD, simulation and optimization are the most powerful – especially when combined in simulation-based optimization (SBO). The aim of this study is to identify the challenges of using SBO in FLD of production systems. To date, the challenges of SBO and FLD have been addressed in separate streams of literature. This paper also presents two novel contributions based on two case studies involving Swedish manufacturers. First, it shows that the challenges of using SBO in FLD identified in the literature are not the most important in industrial environments, where precedence must be given to the challenges of complexity, data noise, and standardization. Second, it shows that the challenges of SBO in FLD are not technological in nature but stem from the increased complexity of the factories required by modern manufacturing companies.