Coronary artery disease (CAD) is a complex multifactorial disorder influenced by both genetic and environmental factors. Genetic research has identified the Apolipoprotein E (APOE) gene as having a crucial role in lipid metabolism and cardiovascular health. The APOE gene, particularly the ε4 allele, has emerged as a significant contributor to CAD susceptibility. This chapter comprehensively examines the current body of research surrounding the association between the APOE ε4 gene variant and CAD risk, while exploring the molecular mechanisms that link this genetic variant to CAD pathogenesis and highlighting the clinical implications. It delves into the molecular mechanisms of how the APOE gene mediates lipoprotein clearance and produces three different isoforms, i.e., APOE2, APOE3, and APOE4, that affect lipid and lipoprotein levels in blood circulation, which influences the risk for CAD pathogenesis. Different populations around the world exhibit different frequencies of APOE isoform distribution correlating with CAD and lipidemias. The chapter explores the impact of different APOE isoforms—APOE2, APOE3, and APOE4 on lipid levels and CAD risk across various populations. The chapter also highlights key clinical manifestations of atherosclerosis, including stable angina, unstable angina, myocardial infarction, and peripheral vascular diseases. Additionally, it examines the role of LDL cholesterol, small LDL particles, and population-based risk assessments, emphasizing that the impact of APOE allelic variations extends beyond CAD to other vascular pathologies.