The publication of To Err Is Human has highlighted concern for patient safety. Attention to date has focused primarily on micro issues such as minimizing medication errors and adverse drug reactions, improving select aspects of care, and reducing diagnostic and treatment errors. However, attention is also required to a macro issue--an organization's culture and the level of leadership required to create a culture. This article discusses the concepts of culture and leadership and summarizes two paradigms that are useful in understanding the precursors of medical errors and developing interventions to prevent them: normal accident theory and high-reliability organization theory. It also delineates approaches to instilling a safety culture. Normal accident theory asserts that errors result from system failures. An important element of this perspective is the need for a system that collects, analyzes, and disseminates information from incidents and near misses as well as regular proactive checks on the system's vital signs. Four subcultures are necessary to support such an environment: a reporting culture, a just culture, a flexible culture, and a learning culture. High-reliability organization theory posits that accidents occur because individuals who operate and manage complex systems are themselves not sufficiently complex to sense and anticipate the problems generated by the system. Lessons learned from high-reliability organizations indicate that a safety culture is supported by migrated distributed decision making, management by exception or negotiation, and fostering a sense of the "big picture." Lessons from other industries are also shared in this article.