Since its discovery, apolipoprotein A-V has been considered to be a potent factor affecting plasma triglycerides (TG) in humans and mice. Several single nucleotide polymorphisms in the APOA5 gene are associated with increased TG levels in humans, and some nonsense mutations affecting protein structure predispose for familial hypertriglyceridemia and late onset chylomicronemia. It is not clear, how apoA-V decreases plasma TG. There are three major hypotheses: apolipoprotein A-V could work through (1) an intracellular mechanism affecting VLDL production in the liver, (2) stimulation of proteoglycan-bound lipoprotein lipase at the endothelium of capillaries in peripheral organs, or (3) enhancing the clearance of TG-rich lipoproteins via lipoprotein receptors in the liver. There is good evidence for a role of apoA-V in extracellular TG metabolism and increasing support for an additional function of ApoA-V as a receptor ligand. The intracellular role of apoA-V for lipoprotein assembly and secretion is still speculative. This review discusses these possible mechanisms. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.