More than 50 years after the Seven Countries Study, a large number of epidemiological studies have explored the relationship between the Mediterranean diet (MD) and health, through observational, case-control, some longitudinal and a few experimental studies. The overall results show strong evidence suggesting a protective effect of the MD mainly on the risk of cardiovascular disease (CVD) and certain types of cancer. The beneficial effects have been attributed to the types of food consumed, total dietary pattern, components in the food, cooking techniques, eating behaviors and lifestyle behaviors, among others. The aim of this article is to review and summarize the knowledge derived from the literature focusing on the benefits of the MD on health, including those that have been extensively investigated (CVD, cancer) along with more recent issues such as mental health, immunity, quality of life, etc. The review begins with a brief description of the MD and its components. Then we present a review of studies evaluating metabolic biomarkers and genotypes in relation to the MD. Other sections are dedicated to observation and intervention studies for various pathologies. Finally, some insights into the relationship between the MD and sustainability are explored. In conclusion, the research undertaken on metabolomics approaches has identified potential markers for certain MD components and patterns, but more investigation is needed to obtain valid measures. Further evaluation of gene-MD interactions are also required to better understand the mechanisms by which the MD diet exerts its beneficial effects on health. Observation and intervention studies, particularly PREDIMED, have provided invaluable data on the benefits of the MD for a wide range of chronic diseases. However further research is needed to explore the effects of other lifestyle components associated with Mediterranean populations, its environmental impact, as well as the MD extrapolation to non-Mediterranean contexts.