Lowering low-density lipoprotein cholesterol (LDL-C) levels remains a mainstay of cardiovascular disease prevention, but gaps in treatment remain, even in persons with hypercholesterolemia and greatly elevated LDL-C levels. Although well-described gene variants in the apolipoprotein B (APOB), low-density lipoprotein receptor (LDLR), and proprotein convertase subtilisin/kexin type 9 (PCSK9) genes explain small but important fractions of monogenic hypercholesterolemia, recent attention has turned to prognostication of cardiovascular disease using polygenic risk scores (PRS) that incorporate common genetic variants derived from large-scale genome-wide association studies of lipid subfractions. Earlier PRS considered only variants with genome-wide significance, and newer studies have focused on methods that better capture the variance conferred by millions of variants, suggesting an ability to identify risk equivalent to monogenic mutations.1 There remains a gap in evidence from prospective observational studies or treatment trials regarding the appropriate placement of PRS in risk assessment and lipid treatment decisions relative to information on rare monogenic gene variants, particularly in multiethnic populations.