The careful clinical characterization of patients with genetic forms of severe hypercholesterolemia has played a critical role in the historic linkage of hypercholesterolemia to atherosclerosis. Elucidation of gene defects that cause severe hypercholesterolemia has provided molecular entrées into the biosynthetic and regulatory pathways that produce and eliminate cholesterol and has led to the development of potent pharmacological agents that dramatically reduce circulating levels of cholesterol. The last decade of the twentieth century culminated in the demonstration that pharmacological reductions in plasma cholesterol levels result in fewer cardiovascular events and reduce total mortality.

This review will summarize recent developments in our understanding of the molecular pathogenesis and treatment of monogenic forms of severe hypercholesterolemia, and some implications that these findings have for the management of common forms of hypercholesterolemia.