PURPOSE OF REVIEW: Apolipoprotein CIII (ApoCIII) is now recognized as a key regulator in severe hypertriglyceridemia, chylomicronemia, and conditions of triglyceride-rich lipoprotein (TRL) remnant excess due to its inhibition of lipoprotein lipase (LPL) and hepatic lipase, leading to decreased hepatic reuptake of TRLs, as well as enhanced synthesis and secretion of VLDL from the liver. ApoCIII gain-of-function mutations are associated with atherosclerosis and coronary heart disease (CHD), and contribute to the development of cardiometabolic syndrome, hypertriglyceridemia, and type 2 diabetes mellitus. Conversely, loss-of-function mutations in ApoCIII are associated with lower levels of plasma triglycerides (TG), attenuation of vascular inflammatory processes such as monocyte adhesion and endothelial dysfunction, and potentially, a reduction in the incidence and progression of atherosclerosis and cardioprotection. RECENT FINDINGS: Evidence is now emerging that volanesorsen, a second-generation antisense oligonucleotide drug targeting ApoCIII messenger RNA resulting in decreases in TG in patients with familial chylomicronemia syndrome, severe hypertriglyceridemia, and metabolic dyslipidemia with type 2 diabetes giving support to the hypothesis that ApoCIII is a powerful inhibitor of LPL, and when reduced, endogenous clearance of TRLs can result in substantial reductions in TG levels. Discovery of the ApoCIII inhibitor volanesorsen opens a new era of lipid-lowering drugs for reduction in TG and potentially for reduction in LDL-C. Herein, this review will provide an update on the pathophysiology of ApoCIII-linked atherosclerosis and the development of the first drug to target ApoCIII, volanesorsen, as a promising lipid-lowering agent.