Traditional simulation-based medical education has often focused on the knowledge, skills, and attitudes of individuals and teams. Increasingly, it is recognized that simulation can also be used to understand, evaluate, and improve complex environments and systems. The objectives, design, and debriefing of system-focused simulation differs in primary purpose and approach from traditional simulation in that it is focused on the physical environment, tasks, tools, technology, people, processes, and organization that surround an individual in a complex system to enable safe and effective care. When used appropriately, system-focused simulation can reduce organizational costs, improve safety and efficiency, inform and reduce risk, as well as solve clinical challenges. This chapter employs four case studies to illustrate these differences and relevant outcomes when viewed through concepts of usability testing and user-centered design.