The National Institutes of Health (NIH), a part of the U.S. Department of Health and Human Services, is the primary Federal agency for conducting and supporting biomedical research. The NIH's mission is to seek fundamental knowledge about the nature and behavior of living systems and to apply that knowledge to enhance health, lengthen life, and reduce illness and disability. In support of this mission, the NIH has invested about $4.2 billion since 2001 in nanotechnology (NT) research. This investment is leading to fundamental changes in understanding biological processes in health and disease, as well as enabling novel diagnostics and interventions for treating disease. NIH scientists are developing molecular agents and methods for earlier and more accurate diagnosis, therapies aimed directly and selectively at diseased cells, and are exploring root causes of common and rare diseases at the proper length scales. Work is underway to move these research tools and devices into clinical practice and to turn personalized medicine into a reality. This chapter provides a brief introduction to the NIH's NT programs since the inception of the National Nanotechnology Initiative. A more comprehensive description of federally funded R&D and their accomplishments is forthcoming.