High-density lipoprotein (HDL) is a “regression particle” based on its unique lipid particle biology. This unique property predicts that, in theory, therapies that raise HDL cholesterol should be able to induce regression of atherosclerosis. Presently, the principle pharmacotherapy for increasing HDL cholesterol is niacin. Niacin has been shown to regress atherosclerosis when used as monotherapy, in combination with a statin, and in combination with nonstatin therapies (including cholesterol-binding resins) and fibrates. Insights into the atherosclerosis benefits of combination lipid-lowering therapy with niacin have come from imaging studies utilizing quantitative coronary angiography, carotid ultrasound, and intravascular ultrasound showing modest inverse correlations between the extent of HDL increase and atherosclerosis regression. Recent adverse atherosclerosis and clinical effects seen with cholesterol ester transfer protein inhibition indicate that HDL-raising effects alone are insufficient to predict clinical benefit of new HDL therapies. Thus, although clinical trial evidence is necessary to understand the full scope of the safety and efficacy profile of novel HDL therapeutics, atherosclerosis imaging will be an important component of preclinical testing of these agents as they emerge and in head-to-head testing of treatment strategies.