LDL cholesterol (LDL-C) measurement is a key component in assessing cardiovascular disease risk and managing dyslipidemia. Despite irrefutable evidence that LDL-C–targeted strategies effectively reduce the risk of cardiovascular events, there is considerable variability among individuals in response to lipid-lowering therapies and in the resulting reduction of cardiovascular risk. Focusing solely on LDL-C assessment and management is no longer an optimal strategy for all patients. A major concern also lies in the potential for substantial errors in risk estimation, given the recognized measurement or calculation inaccuracies of LDL-C in patients with hypertriglyceridemia. Furthermore, the imprecision of calculated or measured LDL-C is less acceptable in the era of new lipid-lowering therapies that achieve very low LDL-C levels. This text, through existing recommendations, highlights the reasons why it has become necessary to use biomarkers beyond LDL-C to identify and treat patients at high cardiovascular risk.