Low levels of high-density lipoprotein cholesterol (HDL-C) represent a major cardiovascular risk factor that is only modestly influenced by currently available drugs. Consequently, there has been interest in developing new therapeutic agents specifically targeting HDL-C to reduce risk in patients with coronary artery disease. One strategy involves the administration of therapies that mimic HDL-C or its properties, including reconstituted HDL, apolipoprotein A-I (apoA-I), apoA-I Milano, and apoA-I mimetic peptides. The atheroprotective effects of reconstituted HDL, apoA-I, and apoA-I Milano have been well documented in animal studies, and two recent clinical trials also provided encouraging results. The most investigated apoA-I mimetic peptide, D-4F, was shown to significantly reduce atherosclerotic lesions in animal models but data in humans are scarce. HDL-C mimetic agents constitute a promising novel strategy to reduce coronary artery disease risk but require further study in larger clinical trials.