The effect of dietary changes on phenotypes (i.e., plasma lipid measures, body weight and blood pressure) differs significantly between individuals. This phenomenon has been more extensively researched in relation to changes in dietary fat and plasma lipid concentrations for the prevention of cardiovascular disease (CVD) compared to other pathological conditions. Although common knowledge associates low fat diets with reductions in total and plasma LDL cholesterol, the clinical evidence shows dramatic inter-individual differences in response that are partially due to genetic factors. The discovery of the cardioprotective and other healthy properties of the Mediterranean diet has popularized the consumption of Mediterranean products such as olive oil. Molecular, clinical, and epidemiological studies have begun to shed some light about how various components of this diet may protect the cardiovascular system and to decrease the risk of other diseases such as cancer. However, it is also possible that the right combination of genetic, cultural, socioeconomic factors is needed to achieve full benefit. It has been proposed that the Mediterranean diet may be closer to the ancestral foods that were part of human development and our metabolism may have evolved to work optimally on such a diet rather than with the current diets richer in saturated fat and highly refined and processed foods. Therefore, it is possible that alleles that are associated with increase disease risk may be silenced in the presence of that more ancestral and traditional diet and lifestyle. This knowledge may provide the basis for successful public health as well individual approaches for disease prevention.