The National Institutes of Health (NIH) is the world's largest biomedical research agency, with a 75-year record of responding to the nation's key medical challenges. Today, medical science is entering a revolutionary period marked by a shift in focus from acute to chronic diseases, rapidly escalating health care costs, a torrent of biological data generated by the sequencing of the human genome, and the development of advanced high-throughput technologies that allow for the study of vast molecular networks in health and disease. This unique period offers the unprecedented opportunity to identify individuals at risk of disease based on precise molecular knowledge, and the chance to intervene to preempt disease before it strikes. Conceptually, this represents the core scientific challenge of the coming century. The NIH is committed to the discoveries that will change the practice of medicine as we know it in order to meet this challenge. The NIH Roadmap constitutes an important vehicle for generating change-a most critical element of this plan is the reengineering of the national clinical research enterprise. This reinvention will call for the transformation of translational clinical science and for novel interdisciplinary approaches that will advance science and enhance the health of the nation.