In nutrition research, analyzing the relationship between a diet-related chronic disease and impaired metabolism is a common reductionist approach. Meta-analyses have enabled quantification of these relationships. There is, however, a need for more holistic approaches to determine the sequence of connections between diseases and associated physiological mechanisms. The objective of this exhaustive review was to collect scientific evidence – with priority given to quantitative reviews – published between 1950 and 2011 to assess the relationships between major diet-related chronic diseases and deregulated mechanisms. The results revealed that diabetes and obesity are the key diseases that lead to all other diet-related chronic diseases, while cancer, cardiovascular disease, skeletal disease, and sarcopenia are endpoint diseases. Liver disease, kidney disease, digestive disease, and mental illness are consequences as well as causes of other diet-related chronic diseases. All diseases have multifactorial causes, and most result from decreased antioxidant status, acid-base imbalance, increased inflammatory status, impaired carbohydrate/lipid/one-carbon metabolism, impaired functioning of neurons and DNA transcription, hypertension, and/or modified digestive microflora. Nutritional strategies that focus on the prevention of obesity and diabetes should be prioritized in order to reduce the prevalence of other major chronic diseases.