During the last decade, approaches to evidence-based medicine, with its heavy reliance on the randomized clinical trial (RCT), have been adapted to nutrition science and policy. However, there are distinct differences between the evidence that can be obtained for the testing of drugs using RCTs and those needed for the development of nutrient requirements or dietary guidelines. Although RCTs present one approach toward understanding the efficacy of nutrient interventions, the innate complexities of nutrient actions and interactions cannot always be adequately addressed through any single research design. Because of the limitations inherent in RCTs, particularly of nutrients, it is suggested that nutrient policy decisions will have to be made using the totality of the available evidence. This may mean action at a level of certainty that is different from what would be needed in the evaluation of drug efficacy. Similarly, it is judged that the level of confidence needed in defining nutrient requirements or dietary recommendations to prevent disease can be different from that needed to make recommendations to treat disease. In brief, advancing evidence-based nutrition will depend upon research approaches that include RCTs but go beyond them. Also necessary to this advance is the assessing, in future human studies, of covariates such as biomarkers of exposure and response, and the archiving of samples for future evaluation by emerging technologies.