Reduced plasma levels of HDL-C are associated with an increased risk of CAD and myocardial infarction, as shown in various prospective population studies. However, recent clinical trials on lipid-modifying drugs that increase plasma levels of HDL-C have not shown significant clinical benefit. Notably, in some recent clinical studies, there is no clear association of higher HDL-C levels with a reduced risk of cardiovascular events observed in patients with existing CAD. These observations have prompted researchers to shift from a cholesterol-centric view of HDL towards assessing the function and composition of HDL particles. Of importance, experimental and translational studies have further demonstrated various potential antiatherogenic effects of HDL. HDL has been proposed to promote macrophage reverse cholesterol transport and to protect endothelial cell functions by prevention of oxidation of LDL and its adverse endothelial effects. Furthermore, HDL from healthy subjects can directly stimulate endothelial cell production of nitric oxide and exert anti-inflammatory and antiapoptotic effects. Of note, increasing evidence suggests that the vascular effects of HDL can be highly heterogeneous and HDL may lose important anti-atherosclerotic properties and turn dysfunctional in patients with chronic inflammatory disorders. A greater understanding of mechanisms of action of HDL and its altered vascular effects is therefore critical within the context of HDL-targeted therapies.