The development of cholesterol-lowering drugs, including a variety of statins, bile acid binding resins and recently discovered inhibitors of cholesterol absorption has expanded the options for cardiovascular disease prevention. However, existing approaches to the treatment of familial hypercholesterolemia (FH) are still ineffective in halting the progression of coronary artery disease (CAD) in some patients despite combination therapies. Homozygous FH (and many heterozygous FH subjects) are resistant to conventional drug treatment and remain at high-risk for development and progression of atherosclerotic cardiovascular disease, therefore alternative approaches are needed. Novel agents that include inhibitors of the apical sodium-dependent bile acid transporter, cholesteryl ester transfer protein, microsomal triglyceride transfer protein and squalene synthase may play a future role in combination with statins. It is possible that with improvements in vector technology, liver-directed somatic gene therapy would be an effective approach for this disorder.