Approach: While the Western diet is proatherogenic, Paleolithic-style diet may be protective against Cardiovascular Diseases (CVDs). Results: Western diet is characterized with energy dense, refined, foods with a high glycemic index (e.g., refined starches; biscuits and bread) and unhealthy lipids (e.g., trans fats, saturated fat, omega-6 rich oils) poor in omega-3 fatty acids, phytochemicals and fibre. These diets are known to predispose inflammation and the epidemic of Non-Communicable Diseases (NCDs). CVD, diabetes mellitus, obesity, cancer and depression, are associated with increased production of Thromboxane A2 (TXA2), leucotrienes, prostacyclin, interleukins-1 and -6, tumor necrosis factor-alpha and C-reactive proteins in the tissues. Increased dietary intake of omega-6 fatty acids is known to enhance all these biomarkers which have adverse pro-inflammatory effects resulting in to CVDs. Functional food approaches including consumption of a Mediterranean diet rich in fruits, vegetables, nuts, canola oil, olive oil characterized with low omega-6/omega-3 ratio in the diet, as well as physical activity and meditation can modulate inflammation as well as body-mind interactions and may be protective against risk of CVD and all-cause mortality. Conclusion: Inflammation appears to be an important unifying hypothesis. In the absence of inflammation in the tissues, total cholesterol and other lipids may have neutral effects in the arterial tissues and myocardium. Therefore, the tissue is possibly the main issue for treatment.