The Office of Dietary Supplements requested the Tufts Medical Center Evidence-based Practice Center (EPC) to conduct an exercise to identify the issues and challenges of including evidence-based methods as a component of the process used to develop nutrient reference values (such as the Dietary Reference Intakes [DRI]) issued by the Institute of Medicine (IOM). This work was performed under a task order issued by the Agency for Healthcare Research and Quality EPC program. The Tufts EPC assembled a group of nutrition experts from academic institutions and relevant federal government agencies, led participants in teleconferences and meetings, conducted exercises in formulating questions that would be amenable to systematic reviews of the scientific literature, and identified the challenges and limitations of applying this method to processes previously used to establish nutrient reference values. This report summarizes the impetus behind this project, approach taken, and the lessons learned. Nutrient reference values have significant public health and policy implications. This type of dietary guidance is needed for planning diets, assessing the adequacy of diets in individuals and populations, developing nutrition education and guidance, and for setting reference values for nutrition labeling. The IOM Food and Nutrition Board has issued reports on the DRIs for a wide range of nutrients. Six reports have been published and are organized around groups of nutrients. Contents of the reports include a summary of what is known about the nutrient function in the human body, selection of indicators of adequacy of nutrient intakes or nutrient levels, factors that may affect how the nutrients are utilized and that affect requirements, and how nutrients may be related to the prevention of chronic disease across age groups. Various study committees were convened to evaluate a body of available scientific evidence for specific nutrients. Primarily human studies were reviewed and selected animal studies were used when human data are absent or conflicting. Available evidence was weighted according to quality, peer review status, biological plausibility, and whether similar estimates would be derived from different indicators. However, the process of establishing DRIs has been variable and has evolved as experience accrued from study committees. Concern has been expressed that in some cases the methods used to determine DRIs have suffered from a lack of transparency and consistency. Moreover, differences in the reference values derived by various groups of nutrition experts worldwide have been noted for the same nutrient when all presumably have used the same body of available evidence. Given the importance of defining reliable nutrient reference values, there is a need for an explicit, objective, and transparent process to set these values. Evaluating evidence is a major component of informing the process. Because new studies are constantly being published, it would also be desirable to have a framework that allows efficient updating when new information becomes available. Although the mandate to different committees around the world has previously been different, with the globalization of the food supply and health risks it should be expected that evaluating similar evidence will result in similar recommendations. Over the past 15 years, the concept of evidence-based medicine building upon the foundation of systematic reviews, meta-analyses and related methods as important tools for evidence-based practice, has gained widespread acceptance in the evaluation of medical evidence for healthcare decision-making. The application of this approach to evaluating the nutrition literature could provide for the transparent, comprehensive and objective evaluation of scientific evidence and could provide support for a framework for a consistent approach to establishing nutrient reference values for all dietary components.