This commentary, written by patient safety expert Lucian Leape, begins with a retrospective view on the birth of patient safety initiatives, the systems approach to addressing problems, progress made in changing systems, and challenges with this systems approach. He discusses the roles accountability, malpractice, and regulation play in patient safety before providing a framework to address ethical concerns in the field. He presents a categorization that includes an imperative to implement and follow safe practices, respond to adverse events and to the injured patient, and take responsibility for problem doctors. The discussion offers an insightful perspective on the complex and important ethical considerations that both support and challenge efforts to improve patient safety.