Health systems are encouraged to strive for zero preventable harm, but achieving this goal requires a comprehensive, systems-focused effort. This paper discusses the rationale for using ‘zero harm’ as a patient safety goal, and the importance of broadening the definition of harm to include non-physical harms (e.g., psychological harms), harms to caregivers and the healthcare workforce, and harms occurring beyond the hospital and across the care continuum. Four key elements required for successful systems change resulting in safety improvements are discussed: (1) change management, (2) culture of safety, (3) a learning system, and (4) patient engagement and codesign of healthcare.