Prospective studies of cardiovascular risk-factors have shown that reduced plasma levels of HDL-cholesterol are associated with increased risk of coronary-disease. Experimental and translational studies have revealed several potential anti-atherogenic effects of HDL, including protective effects of HDL on endothelial cell functions. HDL has been suggested to protect endothelial cell functions by preventing oxidation of LDL and its adverse endothelial effects. Moreover, HDL from healthy subjects can directly stimulate endothelial cell production of nitric-oxide, anti-inflammatory, anti-apoptotic, anti-thrombotic effects, and endothelial-repair processes. Recent clinical-trials using HDL-cholesterol raising agents, such as torcetrapib, dalcetrapib and niacin, could not observe significant reduction of cardiovascular events in patients with coronary-disease. Growing evidence suggests that vascular effects of HDL are highly heterogenous and vasoprotective properties of HDL are altered in patients with coronary-disease. Notably, in recent studies no clear association of higher HDL-cholesterol levels with reduced risk of cardiovascular events was observed in patients with established coronary-disease. Greater understanding of mechanisms of action of HDL and its altered vascular effects is therefore crucial within the context of HDL-targeted therapies. In this review, we will address different effects of HDL on endothelial cell functions potentially relevant to atherosclerotic vascular disease and explore molecular mechanisms leading to dysfunctional HDL.