Other health benefits of olive oil consumption have been related to its anti-neoplasic properties. The second review summarizes the anti-cancer activity of the oleocanthal, a phenolic compound found in extra virgin olive oil. Oleocanthal generally represents about 10% of the total phenolic compounds, ranging from 0.2 mg/kg to 498 mg/kg. Substantial evidence supports the activity of oleocanthal in vitro and in vivo against a wide range of different cancers such as colorectal, breast, melanoma, liver, prostate, and carcinoma. Furthermore, it has been observed that the antineoplastic effects of oleocanthal do not affect the non-tumoral cells. Nor does oleocanthal have any toxicity or side effects when consumed alone or combined with chemotherapeutic agents. The review emphasizes the molecular signaling pathways modulated by oleocanthal in different tumor cell types, including anti-inflammatory action, antioxidant activity, modulation of apoptosis, and inhibition of STAT3, and HGF/c-Met signaling pathways. Noteworthy, the antioxidant and anti-inflammatory effects of oleocanthal play a vital role in the inhibition of cancer initiation and progression. Lastly, several studies have demonstrated that the consumption of long-term micro-doses of oleocanthal, characteristic of the Mediterranean pattern, may diminish the body’s inflammatory response over the years, and therefore may reduce the development of chronic inflammatory diseases, including cancer.