Familial hypercholesterolemia (FH) is a dominantly inherited disorder associated with elevated plasma cholesterol concentrations and premature cardiovascular disease. In addition to impaired low density lipoprotein (LDL) receptor-mediated clearance of low density lipoproteins in FH, evidence from in vitro and in vivo studies suggests that hepatic oversecretion of apoB may contribute to the hypercholesterolemia. The proposed association between apoB secretion and FH may, however, be a function of the class of LDL receptor defect. Hepatic cholesterol pools appear to regulate apoB secretion and LDL receptor activity. Therefore, therapeutic regulation of cholesterogenesis in FH may have the dual effect of reducing hepatic apoB secretion and upregulating the LDL receptor. These effects may also be genetically determined.