The clinical reality of residual risk despite statin (HMG-CoA reductase inhibitor) therapy and emergence of statin intolerance support the need to develop additional lipid-lowering strategies. Proprotein convertase subtilisin kexin type 9 (PCSK9) has received considerable attention by virtue of genetic and clinical studies that have revealed its pivotal role in the regulation of cholesterol homeostasis. Monoclonal antibodies have been developed targeting PCSK9, which have been demonstrated to produce profound low-density lipoprotein cholesterol (LDL-C) lowering when provided as monotherapy or in combination with statins. With the reports that the PCSK9 inhibitor evolocumab has a favorable impact on both plaque progression and cardiovascular outcomes, these findings begin to translate the benefits of PCSK9 inhibition from lipids to the vessel wall and ultimately to clinical outcomes. The clinical implications for the use of these agents are reviewed in this article.