Recent years have seen important improvements in the safety of many areas of health care. However, evidence would suggest that the practice of pediatric sedation outside of the operating room is an area where unaddressed complexities and risks in care remain. In addition, the number of children receiving sedation outside of the operating room is on the increase, emphasizing the need to realize opportunities to improve safety. We outline the risks inherent in sedating children in the context of both the human factors and system factors perspectives. We incorporate examples from other high-technology industries such as aviation and nuclear power generation to allow a better understanding of why things go wrong during sedation, and how safety can be monitored and improved. The value of prior risk assessment, communication, checklists, and formalized recovery pathways are discussed, and new directions for the development of safety initiatives are identified. Finally, a number of practical steps based on existing successful safety approaches are given, with an emphasis on the demonstration of efficacy and the sharing of successful safety solutions.