Reduced HDL cholesterol, commonly found in subjects with obesity and type 2 diabetes, is associated with increased risk of cardiovascular disease (CVD). ApoA-II, a constituent apolipoprotein of certain HDL particles, plays an important role in the regulation of cholesterol efflux, HDL remodelling, and cholesteryl ester uptake via its interactions with lipid transfer proteins, lipases, and cellular HDL receptors. Recent studies have linked apoA-II directly with triglyceride and glucose metabolism. Most of the data are, however, derived from cellular systems and transgenic animal models. Direct evidence from human studies is scarce. Clinical studies demonstrate that apoA-II is a strong predictor of risk for CVD. There is no evidence, however, that selective therapeutic modification of apoA-II impacts on atherosclerosis and clinical outcomes. More research is required to investigate further the significance of apoA-II in clinical medicine.