INTRODUCTION: Angiopoietin-like protein 3 (ANGPTL3) has emerged over the past decade as one of the most intriguing therapeutic targets in lipid metabolism. AREAS COVERED: Genetic deficiency of ANGPTL3 in humans produces a striking pan-hypolipidemic phenotype, with reductions in triglycerides, low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C), accompanied by protection from atherosclerotic cardiovascular disease (ASCVD). These observations rapidly catalyzed the development of pharmacologic strategies to inhibit ANGPTL3 using monoclonal antibodies (e.g. evinacumab), antisense oligonucleotides (e.g. vupanorsen), small interfering ribonucleic acid (e.g. zodasiran and solbinsiran), and most recently genome-editing approaches (e.g. VERVE-201 and CTX310). However, clinical experience has revealed a more complex and context-dependent biology than initially anticipated. EXPERT OPINION: This review examines whether ANGPTL3 should be considered a clinically meaningful cholesterol-lowering target, as exemplified by efficacy of ANGPTL3 inhibition in homozygous familial hypercholesterolemia, or whether its principal therapeutic value lies in modulation of triglyceride-rich lipoproteins and remnant cholesterol, with secondary effects on LDL-C. The degree of hypertriglyceridemia in the patient's baseline lipid profile appears to be an important determinant of drug response. Drawing on genetic, mechanistic, and clinical trial data, the promise and limitations of ANGPTL3 inhibition are considered and its potential place in future lipid-lowering strategies is outlined. A liver protein called ANGPTL3 has become one of the most promising drug targets for new cholesterol-lowering treatments. People born with a natural deficiency of this protein have unusually low levels of all blood fats – including triglycerides and both ‘bad’ (LDL) and ‘good’ (HDL) cholesterol – and are largely protected from heart disease. This sparked intense interest in de