Recent initiatives, such as the Partnership for Patients, focus on reducing the incidence of specific types of adverse events. However, individual adverse events are often interrelated, as patients are vulnerable to multiple types of errors and underlying system flaws can result in different types of patient harm. Recognizing this fact, this commentary calls for a systems engineering approach to identifying and preventing adverse events. This paper was released in conjunction with the announcement of a major new patient safety initiative supported by the Gordon and Betty Moore Foundation.