Epidemiological studies then meta-analyses clearly show that whole grain cereal-based product consumption is globally associated with significant lower prevalence of non-communicable chronic diet-related diseases as obesity, diabetes, CVD and some cancers. Physiological mechanisms behind this protection are complex because whole grain cereals are a complex ‘package’ of bioactive compounds, each one having various potential positive physiological effects. Thus, today, a lot remains to unravel, notably due to synergism of mechanisms. The specific effects of food structure (increased satiety, reduced transit time and glycaemic response), fibre (improved satiety, faecal bulking, digestive viscosity and SCFA production, and/or reduced glycaemic response) and magnesium (better glycaemic homeostasis), together with the antioxidant/anti-carcinogenic/anti-inflammatory properties of numerous compounds, especially those in the bran and germ, are today recognised mechanisms in this protection. Yet, recent findings, exhaustive listing of bioactive compounds found in whole-grain wheat, their content in bran and germ and their estimated bioavailability may lead to propose new hypotheses: 1°) The involvement of polyphenols in cell signalling and gene regulation, and of sulfur compounds, lignin and phytic acid should be considered in antioxidant protection; 2°) Whole-grain wheat is also a rich source of methyl donors and lipotropes (methionine, betaine, choline, inositol and folates) that may be involved in cardiovascular and/or hepatic protection, lipid metabolism and DNA methylation; 3°) the role of fibre co-passengers for delivering bioactive compounds within colon, notably bound phenolic acids; and 4°) The potential protective effects of the B-complex vitamins on mental health, of oligosaccharides as prebiotics, of compounds associated with skeleton health, and of other neglected compounds such as alpha-linolenic acid, policosanol, melatonin, phytosterols and para-aminobenzoic acid would also deserve to be studied in more depth via a synergistic approach. Nutrigenomics to study complex physiological effects of the whole grain ‘package' and interventional studies are therefore needed to move a step forward in the understanding of the mechanisms involved in whole grain cereal protection.