Multiple lines of evidence suggest that the physiologically normal levels of low-density lipoprotein cholesterol (LDL-C) and the thresholds for development of atherosclerosis and adverse coronary events are in the 30- to 70-mg/dl range. More patients have been studied in randomized controlled trials assessing the effects of statins on outcomes than any other drug class in the history of medicine. This cumulative body of evidence documents that atherosclerosis progression is halted and coronary heart disease events are minimized when statin therapy with or without ezetimibe, and possibly proprotein convertase subtilisin–kexin type 9 (PCSK9) inhibitors, is used to drive down the LDL-C to a range of about 30 to 50 mg/dl. Thus far, these agents appear to be safe even when LDL-C is lowered to about 50 mg/dl, although more robust outcome and safety data are required, particularly for the PCSK9 inhibitors and very low LDL-C levels (e.g., down to 25 mg/dl). In conclusion, the current national guidelines specifying only the use of a high-potency statin without specific LDL-C goals may lead to substantial undertreatment of high-risk patients, leaving them vulnerable to future adverse cardiovascular events.