Coronary heart disease is the leading cause of death in the USA and worldwide. Optimizing the ratio and levels of low- and high-density lipoproteins (HDLs) has been a major focus of treatments in preventing atherosclerosis. While these therapies have made significant contributions in reducing heart disease, many patients with normal lipid levels still continue to have significant coronary heart disease and crippling cardiac events. Recent research has brought to light the fact that HDL, widely touted to be protective against atherosclerosis, can actually promote atherogenesis in certain conditions. Disruption of anti-inflammatory properties of HDL may result in atherosclerosis in the presence of decreased, increased or unchanged serum HDL-cholesterol levels. The ability of HDL to prevent or promote atherogenesis can be assessed using a parameter termed the HDL inflammatory index. The next generation of emerging therapeutics, such as apolipoprotein A-I mimetic peptides, will be aimed at improving the anti-inflammatory property of HDL and thus further reducing the incidence of coronary heart disease.