LDL cholesterol (LDL-C) is central to the pathogenesis of atherosclerosis and lowering LDL-C is an important component of cardiovascular disease prevention. This article briefly reviews current LDL-C-lowering strategies and then focuses on novel strategies to reduce LDL-C. Lead compounds of the thyromimetic and squalene synthase inhibitor classes were discontinued due to toxicity. Currently, three novel strategies for LDL-C reduction are in clinical development. Hepatic apoB100 production can be reduced with an antisense oligonucleotide (mipomersen), while production of apoB-containing lipoproteins in the gut and liver is reduced by an inhibitor of microsomal triglyceride transfer protein (lomitapide). apoB-containing lipoprotein clearance can also be enhanced by inhibiting PCSK9. Secreted PCSK9 targets LDL receptors for degradation. As PCSK9 levels are upregulated by statin therapy, PCSK9 inhibition may complement statin therapy. Of the multiple strategies to inhibit PCSK9 under development, monoclonal antibodies have progressed furthest in their clinical development.