Technological advances have enhanced our ability to visualize the entire extent of atherosclerosis within the artery wall. Intravascular ultrasound has enabled characterization of the impact of medical therapies on progression of coronary atherosclerosis. Despite use of established anti-atherosclerotic therapy, cardiovascular disease still remains the leading cause of morbidity and mortality. There is an ongoing need to develop new therapeutic strategies to achieve more effective reduction in cardiovascular risk. Raising high-density lipoprotein cholesterol continues to receive attention as a therapeutic strategy. The relationship between high-density lipoprotein and progression of atherosclerosis and its implications for clinical practice are reviewed here.