Low-density lipoprotein cholesterol (LDL-C) plays a central role in the progression of atherosclerosis. Statin therapy for lowering LDL-C reduces the risk of atherosclerotic cardiovascular disease and is the recommended first-line treatment for patients with high LDL-C levels. However, some patients are unable to achieve an adequate reduction in LDL-C with statins or are statin intolerant; thus, PCSK9 inhibitors were developed to reduce LDL-C beyond statin therapy. PCSK9 monoclonal antibodies dramatically reduce LDL-C levels and cardiovascular risk, and promising new PCSK9 inhibitors using different mechanisms are currently being developed. The absolute benefit of LDL-C reduction depends on the individual absolute risk and the achieved absolute reduction in LDL-C. Therefore, PCSK9 inhibitors may provide the greatest benefits from further LDL-C reduction for the highest risk patients. Here, we focus on PCSK9-targeted therapies and discuss the challenges of LDL-C reduction for prevention of atherogenic cardiovascular disease.