This commentary, written by three leaders in patient safety, discusses the balance between implementing evidenced-based safety practices versus those that make sense but lack literature support. While the authors advocate for many recommendations in the landmark report on safety practices, they caution that waiting for randomized controlled trials will slow necessary and obvious strategies to improve patient safety. They argue that one of the limitations in relying solely on the evidence is a failure to account for interventions that affect systems rather than individuals. The commentary was written as a point–counterpoint to a second commentary in the same issue that emphasized the need for the evidence to drive safety practices. The two articles together provide an excellent overview of the practical challenges that health care organizations face in making decisions about their patient safety programs, the associated costs, and the choices in potentially implementing one practice at the expense of another.