Numerous randomized clinical trials have established statins as the major standard therapy for atherosclerotic diseases because these molecules decrease the plasma level of low density lipoprotein cholesterol and moderately increase the plasma level of high density lipoprotein cholesterol (HDLC). The reverse cholesterol transport (RCT) pathway, mediated by HDL particles, has a relevant antiatherogenic potential. An important approach to HDL-targeted therapy is not optimization of the HDLC level but by improving HDL function, enhancing plasma cholesterol clearance, and preventing and reducing atherosclerosis related inflammation. Small-molecule inhibitors of cholesteryl ester transfer protein increase the HDLC level in subjects with normal or low HDLC. LXR agonists can reduce As by increasing RCT. HDL therapies using reconstituted HDL are dramatically effective in animal models. And, in cell and animal models, studies have found that by interfering with certain gene targets, the cholesterol level and function of HDL can be improved. Our review of the literature leads us to conclude that HDL-targeted therapies have significant atheroprotective potential and thus may effectively treat patients with cardiovascular diseases.