This review addresses two major functions of apolipoprotein (apo) A5 including (1) its role in maintaining normal plasma levels of circulating triglyceride (TG) and (2) its role as a component of hepatic lipid droplets. ApoA5 is synthesized solely in the liver and circulating concentrations are extremely low. In the plasma, ApoA5 associates with TG-rich lipoproteins and enhances TG hydrolysis and remnant lipoprotein clearance. ApoA5 loss-of-function single nucleotide polymorphisms are associated with reduced lipolysis, poor remnant clearance and concomitantly, hypertriglyceridemia. Although there have been substantial breakthroughs in understanding pathophysiology associated with secreted ApoA5, there is a paucity of knowledge on the functionality of intracellular ApoA5. However, recent studies indicate that overexpression of intracellular ApoA5 is positively associated with accumulation of TG-rich lipid droplets in hepatocytes. It is thought that ApoA5 may have a causal role in non-alcoholic fatty liver disease (NAFLD) and thus, may serve as a target for developing therapeutics for NAFLD.