Atherosclerosis is a chronic inflammatory disease affecting medium and large arteries resulting from a complex interaction between genetic and environmental risk factors that include dyslipidemia, hypertension, diabetes mellitus, and smoking. The most serious manifestations of atherosclerotic vascular disease, such as unstable angina, myocardial infarction, ischemic stroke, and sudden death, largely result from thrombosis superimposed on a disrupted (ruptured or eroded) atherosclerotic plaque. Adoption and maintenance of a healthy lifestyle coupled with management of modifiable risk factors significantly reduce the adverse clinical consequences of athero-thrombosis. Reducing low-density lipoprotein cholesterol levels using statins and other agents serves as the primary pharmacologic approach to stabilize atherosclerotic vascular disease. However, a large residual risk remains, prompting the search for additional therapies for atherosclerosis management, such as raising atheroprotective high-density lipoprotein (HDL) and/or improving HDL function. This review focuses on new and emerging HDL-based therapeutic strategies targeting atherosclerosis.