Mendelian randomization studies using naturally occurring genetic variants that raise or lower LDL-C have been instrumental in establishing causality — not just correlation — between LDL-C levels and atherosclerotic disease. Importantly, individuals with inherited variants conferring lifelong lower LDL-C show disproportionately lower ASCVD risk compared to what short-term drug trials would predict, suggesting that duration of LDL-C lowering matters as much as the magnitude. This genetic evidence directly supports starting lipid management earlier in life and is one of the key drivers behind the 2026 ACC/AHA guideline recommendations. Genetic risk scores combining hundreds of LDL-C-associated variants are now being evaluated as clinical tools for early cardiovascular risk stratification.