The final proof about the specific mechanisms by which the different components of olive oil, the principal source of fat in a typical diet”, exert their potential protective effects on the promotion and progression of several human cancers requires further investigations. A recent discovery that dietary fatty acids can interact with the human genome by regulating the amount and/or activity of transcription factors has opened a whole new line of research aimed to molecularly corroborate the ant-cancer benefits of the olive oil-based Mediterranean diet and the underlying mechanisms. Our most recent findings reveal that oleic acid (OA; 18:1n-9), the main olive oils monounsaturated fatty acid, can suppress the overexpression of HER2 (erbB-2), a well-characterized oncogene playing a key role in the etiology, invasive progression and metastasis in several human cancers. First, exogenous supplementation with physiological concentrations of OA significantly down-regulates HER2-coded p185Her-2/neu oncoprotein in human cancer cells naturally harboring amplification of the HER gene. Second, OA exposure specifically represses the transcriptional activity of the human HER2 gene promoter in tumor-derived cell lines naturally exhibiting HER2 gene amplification and p185Her-2/neu protein overexpression but not in cancer cells expressing physiological levels of HER2. Third, OA treatment induces the upregulation of the Ets protein PEA3 (a transcriptional repressor of the HER2 gene promoter) solely in cancer cells naturally displaying HER2 gene amplification. Fourth, HER2 gene promoter bearing a PEA3 site-mutated sequence cannot be negatively regulated by OA, while treatment with OA fails to repress the expression of a human full-length HER2 cDNA controlled by a SV40 viral promoter. Fifth, OA-induced inhibition of HER2 promoter activity does not occur if HER2 gene-amplified cancer cells do no concomitantly exhibit high levels of Fatty Acid Synthase (FASN; Oncogenic antigen- 519) as specific depletion of FASN, which itself similarly suppresses HER2 overexpression by inducing PEA3-dependent repression of HER2 gene promoter, strongly antagonizes the inhibitory effects of OA on HER2 gene promoter activity. Considering that OA treatment efficiently blocks FASN activity and down-regulates FASN protein expression, it is reasonable to suggest that an accumulation of supra-physiological concentrations of the FASN substrate malonyl-CoA, due to its reduced utilization by FASN in the presence of exogenous OA, appears to act as an indicator of fuel” availability capable to suppress HER2 expression via formation of inhibitory protein-PEA3 DNA binding site” complexes on the endogenous HER2 promoter. Indeed, malonyl-CoA on its own dramatically decreases HER2 promoter activity, while OA or malonyl-CoA similarly up-regulates PEA3 gene promoter activity. This previously unrecognized ability of OA to directly affect the expression of a cluster of interrelated human cancer genes (i.e., HER2, FASN and PEA3) should open a new line of research aimed to explore the anti-cancer effects of OA. Certainly, an appropriate dietary intervention reproducing this prominent anti-oncogenic feature of the diet” must be carried out in animal models and human pilot studies in the future. Only then we will know whether the old dietary traditions” will become a new molecular approach in the management of cancer disease.