Serum levels of HDL cholesterol represent a strong, and coherent cardiovascular risk marker seen across all populations, with higher levels of HDL cholesterol being associated with decreased incidence of coronary artery disease. The cardiovascular protective effects of HDL particles are attributed, in great part, to the ability of HDL particles to promote cellular cholesterol efflux from lipid-laden macrophages within the atherosclerotic plaque. HDL also has pleiotropic effects that protect the vascular wall, at least in vitro. These effects include potent anti-inflammatory and antioxidant properties and the modulation of vascular endothelial function. The mechanisms by which HDL exert their function on the vascular endothelium is dependent on HDL particle size, protein (proteome) and lipid (lipidome). The cooperative binding of HDL via SR-BI and G-coupled S1PR1-5 receptors mediates phosphorylation of endothelial nitric oxide synthase at residue 1177 through AKT signaling, preventing uncoupling of NADPH oxidation and nitric oxide synthesis and increasing endothelial nitric oxide synthase abundance. Furthermore, HDL can modulate the activation of NF-κB and the expression of cell adhesion molecules, an early step in endothelial dysfunction. In the present review the authors will focus on the controversies surrounding HDL, clinical treatments and vascular endothelial functions of HDL.