The discovery of proprotein convertase subtilisin kexin-type 9 (PCSK9) and the development of inhibitors of PCSK9 function appear to mark an epochal advance in clinical lipidology. PCSK9 is a circulating protein that binds to low-density lipoprotein (LDL) receptors and facilitates their lysosomal degradation following internalization in cells. Blocking PCSK9 thus increases the recycling of LDL receptors and results in more receptors on the cell surface, particularly in the liver, thereby lowering LDL levels. In this Roundtable, we discuss the recent large cardiovascular outcomes trials in which evolocumab and alirocumab, monoclonal antibodies directed against PCSK9, successfully reduced major cardiovascular events. We discuss the safety of these drugs as well as the safety of maintaining very low LDL cholesterol levels. Finally, we address pragmatic considerations affecting the use of PCSK9 inhibitors in clinical practice.