HDL-replacement therapy is a promising new treatment strategy involving the acute administration of HDL to rapidly stabilize patients at imminent risk for developing a myocardial infarction, such as those with acute coronary syndrome. This review will first focus on the anti-atherogenic mechanisms for HDL, such as the stimulation of the reverse cholesterol transport pathway, and then discuss the other potential beneficial biological effects of HDL on atherosclerosis. The various types of HDL-replacement therapies that are being investigated and developed will be reviewed and ongoing clinical trials and other possible clinical indications for HDL-replacement therapy besides the prevention of myocardial infarction will also be described. Finally, HDL-replacement therapy will be put into perspective by summarizing the current gaps in our knowledge of HDL metabolism and identifying challenges for future research in this area.