Nutritional ecology focuses on the dynamic relationship between humans, nutrition, and the environment. Diet is one of the most critical environmental factors that individuals are exposed to and strongly impacts gene-nutrient interactions. Olives are a valuable product for the Mediterranean Basin countries, and their health benefits have been highly valorized over the years. The drupes are processed mainly to obtain two food products: table olives and olive oil. Olive tree leaves can be directly picked or can also be considered a by-product resulting from farming or processing. Olive oil production generates by-products, such as olive pomace and olive mill wastewaters. Nutraceuticals and dietary supplements using olive products/by-products have also emerged. The main olive polyphenols are hydroxytyrosol, tyrosol, oleocanthal, and oleuropein, and experimental studies have identified molecular targets for these compounds. This chapter highlights the nutrigenomic effects of olive polyphenols, especially hydroxytyrosol, tyrosol, oleocanthal, and oleuropein, on intracellular molecular mechanisms related to the cardiovascular system, lipid metabolism, obesity and type 2 diabetes, inflammatory bowel diseases and microbiota, osteoarthritis, Alzheimer’s disease, and cancer.