Purpose of Review: The Friedewald equation for estimation of low-density lipoprotein cholesterol (LDL-C) was published in 1972 as an alternative to direct assessment by preparative ultracentrifugation. In this equation, very low-density lipoprotein is estimated by dividing triglycerides by a fixed factor (5 in mg/dL or 2.2 in mmol/L) and subtracting this term from non-high-density lipoprotein cholesterol (non-HDL-C). This method was derived in fasting samples from a small cohort of patients with primarily genetic dyslipidemias followed at the NIH. The method served well as the global standard for LDL-C estimation for decades, but is not well suited to modern clinical practice because it tends to underestimate LDL-C at low LDL-C and high triglyceride levels. The concern is that underestimation could lead to undertreatment in high-risk patients. Recent Findings: Derived from big data and now validated around the world, a novel LDL-C equation created at Johns Hopkins replaces the fixed factor seen in the classic equation with a patient-specific variable based on triglyceride and non-HDL-C levels. Summary: Given its superior accuracy in fasting and non-fasting populations alike, the novel equation is now the preferred method for LDL-C estimation and is being incorporated by leading clinical laboratories.