Several epidemiological studies have shown that an increase in fibrinogen levels is associated with the risk of cardiovascular disease. Recently, it has been demonstrated that the levels of fibrinogen can be genetically determined. Overall the studies show a strong association between two polymorphisms of the fibrinogen beta-chain gene and fibrinogen plasma concentration. Few studies have, in contrast, found an association between such polymorphisms and the risk of ischemic vascular disease. Rather than directly affecting the levels of proteins or the risk of disease, polymorphisms can amplify the effect of environmental or intermediate conditions on the final phenotype. The genetic control of fibrinogen has to be considered together with environmental factors: fibrinogen genotypes may interact with cigarette smoking, gender, physical activity, use of drugs and infections in determining the increase in fibrinogen levels and perhaps the risk of ischemic heart disease. Three examples are presented supporting the concept that, in multifactorial diseases, genetic variability influences the risk of disease by determining a different individual susceptibility to environmental risk factors.