Evidence is synthesized that foods and food patterns act synergistically to influence the risk of several chronic diseases. Whole-grain consumption and risk of disease are presented as a model of food synergy. Food synergy is defined as additive or more than additive influences of foods and food constituents on health. Risk appears to be lower with consumption of whole grain than of refined grain; that is, benefit accrues when all edible parts of the grain are included (bran, germ, and endosperm). It appears that phytochemicals that are located in the fiber matrix, in addition to or instead of the fiber itself, are responsible for the reduced risk. Risk is further reduced if whole-grain foods are consumed in a diet otherwise high in plant foods. To gain full understanding of the pathways by which food synergies work, it is desirable to use several “top down” approaches, starting with the larger units, namely foods or food patterns, and working down to smaller units that provide protection from disease. Study of foods, food patterns, and individual nutrients or food components in reducing disease risk is seen as complementary. Epidemiologic, clinical trial, and in vitro approaches to such research are needed.