There are multiple guidelines for managing patients with high-risk cardiovascular disease, and unfortunately for the practicing clinician, these guidelines are quite variable. Some are fairly specific whereas others are not, resulting in a great deal of confusion regarding whether management of low-density lipoprotein cholesterol (LDL-C) should be tailored only, targeted only, or managed by a combination of both. In the management of cardiovascular disease, favorable cardiovascular outcomes can be obtained by simply lowering the LDL-C in the absence of any other medications. The advent of statins, the most potent LDL-C-lowering medication yet when developed, provided benefits augmented by the presence of multiple pleiotropic effects. Tailoring and/or targeting the decrease in LDL-C is also an issue of concern. Then, in 2016, the new proprotein convertase sutilisin-like/kexin type 9 (PCSK9) inhibitors appeared, providing a solution to patients with high-risk cardiovascular disease with statin intolerance and those who did not attain a desired LDL-C level while on a high-dose statin. These new PCSK9 inhibitors necessitate a determination of how low the LDL-C can and should go, most likely safely down to a beneficial level of 25 mg/dL for the highest-risk patient. These issues are documented and discussed with an attempt to help the reader make an informed risk management decision.