Plasma levels of high-density lipoprotein (HDL) cholesterol are inversely associated with risk of atherosclerotic cardiovascular disease in humans, but recently the field has shifted from a focus on HDL-C concentrations to HDL function. HDL is believed to protect against atherosclerosis by promoting reverse cholesterol transport, as well as potentially through a variety of other protective properties. However, despite advances over the last decade, the molecular regulation of HDL metabolism and reverse cholesterol transport (RCT) remain incompletely understood, the relevance of other HDL properties remains uncertain, and the concept of directly targeting HDL therapeutically in humans remains unproven. Genome-wide association studies (GWAS) have established that all three members of the subfamily of extracellular lipases that act on lipoproteins, lipoprotein lipase (LPL), hepatic lipase (HL), and endothelial lipase (EL), are significantly associated with variation in lipid traits including HDL-C levels. Furthermore, it is becoming clear that these lipases are finely regulated by a series of other proteins such as CETP, PLTP, ANGPTL3 and ANGPTL4. In fact, both common and low frequency genetic variants in all of the above genes have been shown to have highly significant associations with plasma TG and/or HDL-C levels, and in some cases with CAD. Our investigations into the roles of EL, HL and LPL, and their interactions with other proteins in modulating triglyceride and HDL metabolism, reverse cholesterol transport, and atherosclerosis span biochemical, cell biology, mouse and human translational studies in addressing the relevant questions. This subfamily of lipases is a potential target for novel therapeutic development, and these studies will provide greater understanding of their effects on HDL metabolism and function, enabling future treatments to prevent atherosclerosis.