This report describes the efforts of the Secretary’s Advisory Committee on Genetics, Health, and Society (SACGHS) to assess the need and readiness for a new large population study (LPS) in the United States and presents recommendations to the Secretary of the U.S. Department of Health and Human Services (HHS) so that this concept can be further explored. The HHS Secretary established SACGHS in 2002 as a public forum for deliberation on the broad range of human health and societal issues raised by advances in genetics and, as warranted, the development of advice on these issues. In a March 2004 priority-setting process, SACGHS identified 11 high-priority issues warranting its attention and analysis. One of those issues was the need for an analysis of the opportunities and challenges associated with conducting an LPS aimed at understanding the relationships between genes, environments,1 and their interactions and common complex diseases. Among the considerations that led the Committee to this decision was the fact that discussions were underway at the National Institutes of Health (NIH) about whether the United States should mount a new large population-based study. In June 2005, as SACGHS factfinding efforts were beginning, NIH Director Dr. Elias A. Zerhouni requested that the Committee develop a report on the preliminary questions, steps, and strategies that would need to be addressed before considering the larger question of whether the United States should undertake a new LPS. Specifically, the Committee was asked to (1) delineate the questions that need to be addressed for policymakers to determine whether the U.S. Government should undertake a new LPS to elucidate the influences of genetic variations and environmental factors on common complex diseases; (2) explore the ways in which, or processes by which, the questions identified in step 1 can be addressed, including any intermediate research studies, pilot projects, or policy analysis efforts needed; and (3) determine the possible ways in which these questions could be addressed, taking into account the feasibility of those approaches expect the Committee to recommend solutions to the questions raised. The next section summarizes exploratory work by the National Human Genome Research Institute (NHGRI) and factfinding and consultative efforts by SACGHS on this issue. Chapter II presents the scientific basis for an LPS. Chapter III outlines the key policy issues that SACGHS has identified as warranting further attention. Chapter IV discusses the critical role that public engagement must play in determining the willingness of U.S. citizens to support and participate in such an endeavor. In keeping with its agreed upon charge, throughout this report the Committee explores the ways in which the identified policy issues could be addressed and describes possible approaches for the HHS Secretary’s consideration.