The Institute of Medicine’s report “To Err is Human” identified simulation as a means to enhance safety in the medical field, just as flight simulation is used to improve the aviation industry. Yet, while there is evidence that simulation may improve task performance, there is little evidence that simulation actually improves patient outcome. Similarly, simulation is currently used to model teamwork-communication skills for disaster management and critical events, but little research or evidence exists to show that simulation improves disaster response or facilitates intersystem or interagency communication. Simulation ranges from the use of standardized patient encounters to robot-mannequins to computerized virtual environments. As such, the field of simulation covers a broad range of interactions, from patient–physician encounters to that of the interfaces between larger systems and agencies. As part of the 2008 Academic Emergency Medicine Consensus Conference on the Science of Simulation, our group sought to identify key research questions that would inform our understanding of simulation’s impact at the organizational level. We combined an online discussion group of emergency physicians, an extensive review of the literature, and a “public hearing” of the questions at the Consensus Conference to establish recommendations. The authors identified the following six research questions: 1) what objective methods and measures may be used to demonstrate that simulator training actually improves patient safety? 2) How can we effectively feedback information from error reporting systems into simulation training and thereby improve patient safety? 3) How can simulator training be used to identify disaster risk and improve disaster response? 4) How can simulation be used to assess and enhance hospital surge capacity? 5) What methods and outcome measures should be used to demonstrate that teamwork simulation training improves disaster response? and 6) How can the interface of systems be simulated? We believe that exploring these key research questions will improve our understanding of how simulation affects patient safety, disaster surge capacity, and intersystem and interagency communication.