Our knowledge of the composition of phenolic compounds present in olive oil has been profoundly increased in recent years due to sophisticated analytical technologies. These compounds have been clearly shown in vitro to possess strong antioxidant and free-radical scavenging activity. Moreover, recent studies have evidenced that these compounds are absorbed, metabolised and transported in lipoproteins. A great deal of experimental work has evidenced potential roles for these compounds in protecting the cardiovascular system: 1) by direct antioxidant defence, especially against lipid peroxidation and DNA oxidative damage; 2) by preventing endothelial dysfunction, including increased nitric oxide (NO) production and inducible NO synthesis, and quenching vascular endothelium intracellular free radicals; 3) by inhibiting platelet-induced aggregation; 4) by enhancing the mRNA transcription of the enzymes involved in antioxidant defence; 5) by inducing apoptosis and anti-proliferative effects; 6) by presenting antimicrobial and antiviral activity and modulating immune system function. In animal models, emerging beneficial effects on the control of blood pressure have been observed, but conflicting results on the role of olive phenolics in the management of atherosclerosis are also presented. In conclusion, research has robustly shown that these natural chemical compounds may play important roles in vivo but much effort still remains to be done before a definitive recommendation regarding their use in clinical settings.