FAME investigators discuss in a recent review nutritional implications of the intake and metabolism of omega-3 and omega-6 polyunsaturated fatty acids for cardiometabolic diseases (Schulze et al. Lancet Diabetes Endocrinol 2020). While prospective observational studies support the use of long-chain omega-3 PUFAs in the primary prevention of cardiovascular disease, randomised controlled trials have often reported neutral findings. The harmful effects of a high intake of omega-6 PUFAs are debated, although this idea is not supported by prospective studies. Health effects of PUFAs might be influenced by desaturases, the key enzymes in the metabolism of PUFAs. The activity of these enzymes and modulation by variants of the FADS1-2-3 gene cluster are linked to several cardiometabolic traits.The review discusses the consequences of altered desaturase activity in the context of PUFA intake and their clinical and public health implications.