Genetic variation at the APOE locus has been associated with plasma lipoprotein concentrations in the fasting (low-density, and high-density lipoproteins and triglycerides), and in the postprandial (triglyceride-rich lipoproteins) states. Resulting from these associations, the APOE locus has been found to be a significant genetic determinant of cardiovascular disease in the general population. Beyond the traditional association studies, APOE genetic variation has been shown to play a significant role, which explains some of the individual variations in therapies aimed at normalizing plasma lipid concentrations. Thus, the APOE E4 allele has been shown in some studies to be associated with increased response to dietary intervention. Conversely, APOE E2 carriers appear to be more responsive to statin therapy. The mechanisms behind these observations, however, have not been elucidated. Moreover, several other gene:environment and gene:therapy interactions have recently been demonstrated, thus further increasing the interest in this remarkable apolipoprotein.