Mendelian randomization studies and randomized trials have conclusively demonstrated that lower low-density lipoprotein (LDL) cholesterol results in fewer cardiovascular events. This review describes key stages in the evolution of LDL cholesterol-lowering treatment. Data from over 25 cardiovascular outcome trials confirm that, within a few years, statins lower the relative risk of major atherosclerotic events by about 22% per 38.7 mg/dl (1 mmol/l) reduction in LDL cholesterol, with similar benefit across patient subgroups. Meta-analyses of these trials have established the safety of statins with regard to nonvascular mortality and cancer. Other agents available for prescription include ezetimibe and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, which both reduce major atherosclerotic events in proportion to their effects on LDL cholesterol and have good safety profiles, though PCSK9 inhibitors remain costly. Investigational LDL cholesterol-lowering agents currently being tested in cardiovascular outcome studies are bempedoic acid, an adenosine triphosphate-citrate lyase inhibitor that reduces cholesterol synthesis, and inclisiran, a double-stranded small interfering ribonucleic acid that inhibits PCSK9 synthesis.