Purpose of Review <p>The angiopoietin-like protein (ANGPTL) 3–4–8 axis has emerged as a central regulator of lipoprotein lipase and lipid metabolism. This review examines the mechanistic basis of ANGPTL pathway modulation and therapeutic implications for cardiovascular risk reduction across diverse phenotypes of dyslipidemia.</p> Recent Findings <p>Genetic studies demonstrate that loss-of-function variants in ANGPTL3 and ANGPTL4 are associated with lower triglycerides and decreased coronary artery disease risk. Pharmacologic inhibition of ANGPTL3 with monoclonal antibodies and RNA-based therapies reduces triglycerides, remnant cholesterol, low-density lipoprotein cholesterol (LDL-C), and apolipoprotein B (apoB) through mechanisms predominantly independent of the LDL receptor. Clinical trials with ANGPTL3 inhibitors have demonstrated marked LDL-C reductions in patients with homozygous familial hypercholesterolemia (HoFH), as well as broad lipid-lowering effects in patients with mixed dyslipidemia. Emerging strategies targeting the ANGPTL3/8 complex and ANGPTL4 further refine lipid-lowering effects, while early genome-editing data suggest the potential for durable ANGPTL3 suppression.</p> Summary <p>Modulation of the ANGPTL–lipoprotein lipase axis is a novel strategy to address residual atherosclerotic risk beyond traditional LDL receptor–dependent therapies. ANGPTL3 inhibitors have been practice-changing in HoFH, and more broadly, ANGPTL-directed therapies hold promise for patients with mixed dyslipidemia to mitigate cardiovascular risk.</p>