Over the millennia, patterns of food consumption have changed; however, foods were always whole foods. Ultra-processed foods (UPFs) have been a very recent development and have become the primary food source for many people. The purpose of this review is to propose the hypothesis that, forsaking the evolutionary dietary environment, and its complex milieu of compounds resulting in an extensive metabolome, contributes to chronic disease in modern humans. This evolutionary metabolome may have contributed to the success of early hominins. This hypothesis is based on the following assumptions: (1) whole foods promote health, (2) essential nutrients cannot explain all the benefits of whole foods, (3) UPFs are much lower in phytonutrients and other compounds compared to whole foods, and (4) evolutionary diets contributed to a more diverse metabolome. Evidence will be presented to support this hypothesis. Nutrition is a matter of systems biology, and investigating the evolutionary metabolome, as compared to the metabolome of modern humans, will help elucidate the hidden connections between diet and health. The effect of the diet on the metabolome may also help shape future dietary guidelines, and help define healthy foods.