Hypercholesterolemia is a major risk factor for atherosclerosis. Low-density lipoprotein cholesterol (LDL-C) lowering drugs reduce cardiovascular morbidity and mortality. However, many individuals treated with statins do not achieve their target levels of LDL-C. So, there is great need for new drugs to reduce cholesterol in those patients who have not achieved target levels with statins as well as those who are statin intolerant. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a novel agent, which plays an important role in the regulation of cholesterol metabolism. It increases degradation of the low-density lipoprotein receptor, modulates cholesterol metabolism, and transport. This review will address new therapeutic strategies targeting PCSK9, including monoclonal antibodies, small interfering RNAs, and other small molecule inhibitors.