Achieving dramatic, sustainable improvements in the safety and effectiveness of care for children requires a transformational approach to how hospitals individually focus on improvement and learn from each other to achieve national goals. The authors describe a theoretic framework for transformation that includes setting system-level priorities, aligning measures with each priority, identifying breakthrough targets, testing interventions to get results, and spreading successful interventions throughout the organization. Essential key drivers of transformation include leadership, building will, transparency, a business case for quality, patient and family engagement, improvement infrastructure, improvement capability, and reliability and standardization. Improving national system-level measures requires each hospital to pursue its own transformation journey while collaborating with hospitals and other organizations.