Nutrigenomics data on the functional components of olive oil are still sparse, but rapidly increasing. Olive oil is the main source of fat and health-promoting component of the Mediterranean diet. Positive effects have been observed on genes involved in the pathobiology of most prevalent age- and lifestyle-related human conditions, such as cancer, cardiovascular disease and neurodegeneration. Other effects on health-promoting genes have been identified for bioactive components of olives and olive leafs. Omics technologies are offering unique opportunities to identify nutritional and health biomarkers associated with these gene responses, the use of which in personalized and even predictive protocols of investigation, is a main breakthrough in modern medicine and nutrition. Gene regulation properties of the functional components of olive oil, such as oleic acid, biophenols and vitamin E, point to a role for these molecules as natural homeostatic and even hormetic factors with applications as prevention agents in conditions of premature and pathologic aging. Therapeutic applications can be foreseen in conditions of chronic inflammation, and particularly in cancer, which will be discussed in detail in this review paper as major clinical target of nutritional interventions with olive oil and its functional components. © 2016 BioFactors, 43(1):17-41, 2017.