We have witnessed the separation of the care for an individual patient and the concern for the health of a population. As we anticipate the twenty-first century, we see the wisdom of reconnecting these concerns. The knowledge and skills that we will address can help bridge the gap. First, we offer background to seminal work during the twentieth century that set the foundation for the improvement of health care. Next, we describe two major challenges for the continual improvement of health care that lie ahead. Third, we suggest an approach that leaders might use to address major challenges. Fourth, we offer a set of knowledge domains that outline the knowledge and skills that leaders of the improvement of health care will need. Finally, we provide two special issues that require additional mention and should not be overlooked. We believe that the combination of these ideas can provide a framework for knowledge building, action taking, and reflection needed by health care leaders in the coming century.