One hundred years ago a series of seminal documents, starting with the Flexner Report of 1910, sparked an enormous burst of energy to harness the power of science to transform higher education in health. Professional education, however, has not been able to keep pace with the challenges of the 21st century. A new generation of reforms is needed to meet the demands of health systems in an interdependent world. The report of the Commission on the Education of Health Professionals for the 21st Century, a global independent initiative consisting of 20 leaders from diverse disciplinary backgrounds and institutional affiliations, articulates a fresh vision and recommends renewed actions. Building on a rich legacy of educational reforms during the past century, the Commission's findings and recommendations adopt a global and multi-professional perspective using a systems approach to analyze education and health, with a focus on institutional and instructional reforms.