Low plasma HDL cholesterol levels are an independent risk factor for atherosclerotic cardiovascular disease. During the past years, the study of HDL has been stimulated by the discovery of novel genes and proteins, which have provided new insights into the molecular and cellular mechanisms involved in HDL metabolism. In addition, recent clinical studies focused on treating low HDL as primary objective in high cardiovascular risk patients have been very encouraging. Furthermore, new drugs for raising HDL cholesterol are under development. This article reviews the recent progress in the HDL field and its important implications for the pathophysiology and treatment of atherosclerosis. In the near future, we expect that new drugs with specific and beneficial effects on HDL metabolism and the associated cardiovascular risk should improve the current approach to this disease with high burden on health systems and society.