Hypercholesterolemia is a key risk factor for atherosclerosis. Because of its role in controlling serum levels of low-density lipoprotein (LDL) through the regulation of hepatic LDL-receptors, the recently discovered proprotein convertase subtilisin/kexin-type 9 (PCSK9) is a promising pharmacological target. This review aims to discuss the impact of natural mutations in the PCSK9 gene on cholesterol metabolism and thus coronary artery disease, as well as molecular mechanisms and therapeutic strategies for PCSK9 inhibition. We summarize data from recent clinical trials using fully humanized monoclonal antibodies, showing that PCSK9 inhibition results in a significant reduction in LDL-cholesterol in high-risk cardiovascular patients. Future studies will have to address the long-term safety and efficacy as well as the impact of PCSK9-targeting therapies on cardiovascular outcomes.