The Mediterranean diet, in which olive oil is the primary source of fat, is associated with a low mortality for cardiovascular disease. Data concerning olive oil consumption and primary end points for cardiovascular disease are scarce. However, a large body of knowledge exists providing evidence of the benefits of olive oil consumption on secondary end points for the disease. Besides the classical benefits on the lipid profile provided by olive oil consumption compared with that of saturated fat, a broad spectrum of benefits on cardiovascular risk factors is now emerging associated with olive oil consumption. We review the state of the art concerning the knowledge of the most important biological and clinical effects related to olive oil and its minor components. The recent advances in human nutrigenomics associated with olive oil consumption will also be assessed. The wide range of benefits associated with olive oil consumption could contribute to explaining the low rate of cardiovascular mortality found in southern European-Mediterranean countries, in comparison with other westernized countries, despite a high prevalence of coronary heart disease risk factors.