Reduced levels of high-density lipoprotein cholesterol (HDL) are associated with a substantially increased risk of coronary disease and cardiovascular events. Furthermore, numerous studies have suggested that HDL may exert several potentially important antiatherosclerotic and endothelial-protective effects. In particular, the promotion of reverse cholesterol transport, i.e. cholesterol efflux from lipid-loaded macrophages in atherosclerotic lesions and the subsequent cholesterol transport back to the liver, has been proposed as an anti-atherogenic effect of HDL that may promote regression of atherosclerotic lesions. Moreover, endothelial dysfunction is thought to play a critical role in development and progression of atherosclerosis and several recent studies have suggested that HDL exerts direct endothelial-protective effects, such as stimulation of endothelial production of the anti-atherogenic molecule nitric oxide, anti-oxidant, anti-inflammatory and anti-thrombotic effects. Furthermore, it has been observed that HDL may stimulate endothelial repair processes, involving mobilisation and promotion of endothelial repair capacity of endothelial progenitor cells. The relative significance of these different potential anti-atherosclerotic effects of HDL remains still unclear at present. Importantly, at the same time it has been recognized that the vascular effects of HDL may be variable, i.e. the capacity of HDL to stimulate macrophage cholesterol efflux and endothelial-protective effects may be altered in patients with inflammatory or cardiovascular disease. The further characterisation of underlying mechanisms and the identification of the clinical relevance of this “HDL dysfunction” are currently an active field of research. HDL-targeted treatment strategies are at present intensely evaluated and may lead to increased HDL plasma levels and/or HDL-stimulated anti-atherosclerotic effects. The cardiovascular protection provided by such approaches may likely depend on HDL function or quality, i.e. the anti-atherosclerotic and endothelial-protective properties of the on-treatment HDL. Currently, several HDL-raising treatment strategies are examined in clinical trials, i.e. extended-release niacin, the CETP inhibitors dalcetrapib and anacetrapib, reconstituted forms of HDL (i.e. CSL-111) or apoA-I mimetics, and some of these are already in large clinical outcome studies on top of statin therapy to determine their efficacy and safety for cardiovascular prevention.