The tissue composition of polyunsaturated fatty acids (PUFA) is important to health and depends on both dietary intake and metabolism controlled by genetic polymorphisms that should be taken into consideration in the determination of nutritional requirements, obesity and chronic disease risk. Experimental and clinical intervention studies suggest that omega-6 and omega-3 fatty acids have opposing physiological and metabolic properties and elicit divergent effects on body fat gain through mechanisms of adipogenesis, browning of adipose tissue, lipid homeostasis, systemic inflammation and an increase in the tone of the endocannabinoid system. Overweight and obese individuals have higher levels of the arachidonic acid (AA) derived endocannabinoid N-arachidonoylethanolamine (AEA) and 2-arachidonoylglycerol (2-AG) and an altered pattern of receptor expression. Since endocannabinoids are products of dietary fats, modification of the omega-6 and omega-3 fatty acid intake modulates the endocannabinoids, with eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) displacing AA from cell membranes, reducing AEA and 2-AG production, resulting in decrease in appetite and food intake leading to weight loss. Polygenic risk scores reveal susceptibility and an increase risk for obesity. Therefore, persons at risk for obesity will have to lower omega-6 and increase their omega-3 fatty acid intake in order to have a balanced ratio for health. A process needs to be established to define when genomic discoveries such as gene-nutrient-disease associations are “ready” to be evaluated as potential tools for personalized nutrition to improve public health.