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To reduce the increased burden of diet-related disease and promote human potential through food and nutrition globally, harmonization of efforts is urgently needed. This article examines the concept of food-based dietary guidelines (FBDGs) and discusses the possibilities and challenges of harmonizing the process of developing and implementing dietary guidelines. The authors argue that while the development of FBDGs has contributed to the understanding of the role of nutrients and foods in achieving optimal health, the impact of these guidelines on human health has been limited. Science or evidence must be used in FBDG development; nevertheless, there are limitations in current nutrition science. FBDGs should address the health consequences of dietary insufficiency, excess, or imbalance with a broader perspective, considering the totality of the effects of a given dietary pattern, rather than focusing on single nutrients alone. Moreover, the food selection guideline should be seen as complementary to a strategic, comprehensive, and culturally appropriate dietary and health promoting intervention, and not only as a tool for providing nutrition policy and information. Technically, a single unified global set of FBDGs may be desirable and even achievable. This concept, however, presents novel challenges on how to address cultural diversity and the complex social, economic, and political interactions between humans and the food supply, not to mention the complexity of its communication and implementation. Therefore, global harmonized efforts in support of strategic dietary interventions, together with strong global scientific support and facilitation for the development and communication of FBDGs at national or regional levels, are proposed to implement FBDGs for healthier populations.