Variants in the FADS gene cluster modify the activity of polyunsaturated fatty acid ( PUFA) desaturation and the lipid composition in human blood and tissue. FADS variants have been associated with plasma lipid concentrations, risk of cardiovascular diseases, overweight, eczema, pregnancy outcomes, and cognitive function. Studies on variations in the FADS gene cluster provided some of the first examples for marked gene-diet interactions in modulating complex phenotypes, such as eczema, asthma, and cognition. Genotype distribution differs markedly among ethnicities, apparently reflecting an evolutionary advantage of genotypes enabling active long-chain PUFA synthesis when the introduction of agriculture provided diets rich in linoleic acid but with little arachidonic and eicosapentaenoic acids. Discovering differential effects of PUFA supply that depend on variation of FADS genotypes could open new opportunities for developing precision nutrition strategies based either on an individual's genotype or on genotype distributions in specific populations.