BACKGROUND: Improving health in our nation requires strengthening four major domains of the health care system: personal health management, health care delivery, public health, and health-related research. Many avoidable shortcomings in the health sector that result in poor quality are due to inaccessible data, information, and knowledge. A national health information infrastructure (NHII) offers the connectivity and knowledge management essential to correct these shortcomings. Better health and a better health system are within our reach. DISCUSSION: A national health information infrastructure for the United States should address the needs of personal health management, health care delivery, public health, and research. It should also address relevant global dimensions (e.g., standards for sharing data and knowledge across national boundaries). The public and private sectors will need to collaborate to build a robust national health information infrastructure, essentially a 'paperless' health care system, for the United States. The federal government should assume leadership for assuring a national health information infrastructure as recommended by the National Committee on Vital and Health Statistics and the President's Information Technology Advisory Committee. Progress is needed in the areas of funding, incentives, standards, and continued refinement of a privacy (i.e., confidentiality and security) framework to facilitate personal identification for health purposes. Particular attention should be paid to NHII leadership and change management challenges. SUMMARY: A national health information infrastructure is a necessary step for improved health in the U.S. It will require a concerted, collaborative effort by both public and private sectors.