Although elevated levels of cholesterol are associated with increased risks of coronary and peripheral vascular disease, the association frequently fails to provide a causative explanation at the individual level. New hypotheses are required which, whether or not they are correct, will provide new lines of research. It is proposed here that the causes of vascular disease are abnormal membrane phospholipid concentrations of the 20-carbon and 22-carbon essential fatty acids (EFAs) of the n-6 and n-3 series. These levels become abnormal with ageing, with stress and in response to smoking, high cholesterol levels and high saturated fat intakes. They are also abnormal in patients with diabetes and hypertension. The effects of these EFAs and their metabolites include lowering of triglycerides, elevation of high-density lipoprotein (HDL)-cholesterol, reduction of blood pressure, vasodilatation, reduction of fibrinogen levels and inhibition of platelet aggregation and of cardiac arrhythmias. Prospective studies have shown that abnormal levels of these fatty acids are predictive of future coronary death. Controlled trials of treatment have demonstrated that provision of the fatty acids reduces both coronary and total mortality. Further experimental and clinical investigations of the roles of appropriate membrane concentrations of these fatty acids are justified.