High-density lipoprotein (HDL) has been identified as a potential target in the treatment of atherosclerotic vascular disease. The failure of torcetrapib, an inhibitor of cholesteryl ester transfer protein (CETP) that markedly increased HDL levels in a clinical trial, has called into doubt the efficacy of HDL elevation. Recent analysis suggests that failure may have been caused by off-target toxicity and that HDL is functional and promotes regression of atherosclerosis. New studies highlight the central importance of the ATP-binding cassette (ABC) transporters ABCA1 and ABCG1 in reducing macrophage foam cell formation, inflammation, and atherosclerosis. A variety of approaches to increasing HDL may eventually be successful in treating atherosclerosis.