Abstract: High plasma levels of Low Density Lipoprotein Cholesterol ( LDL-C) triglycerides and low levels of High Density Lipoprotein Cholesterol ( HDL-C) are strong and independent risk factors for Coronary Heart Disease (CHD). The first two abnormalities are managed by diet and a variety of drugs including statins cholesterol absorption inhibitors fibrates and niacin. Some of these drugs also elevate HDL albeit poorly. Appropriate treatments for HDL elevation are still needed. Low HDL-C is a common lipoprotein abnormality in patients with CHD. HDL mediates a broad variety of antiatherogenic effects within the cardiovascular system. An important antiatherogenic function of HDL is its ability to stimulate reverse cholesterol transport a process by which HDL is able to translocate excess cholesterol mass from cells within the subendothelial space and atheromatous plaque and deliver it back to the liver for elimination via the gastrointestinal tract. Among other functions HDL stimulates endothelial nitric oxide production and vasodilatation it is antithrombotic by reducing platelet aggregability and prostacyclin production. HDL also inhibits endothelial cell apoptosis reduces the oxidation of fatty acids in LDL-C particles and inhibits the expression of endothelial Cells Adhesion Molecules (ICAM-1 VCAM-1). Prospective epidemiologic studies indicate that high serum levels of HDL-C are atheroprotective while low levels of HDL-C are associated with increased risks for atherosclerotic disease and its clinical sequelae. Research in the past decade has greatly enhanced our understanding of HDL metabolism and has consequently offered potential therapeutic targets to address low HDL syndrome. Many new drugs and systems for treating patients with low HDL-C are currently being developed. HDL mimetics edible HDL Cholesterol Ester Transfer Protein (CETP) inhibitors endocannabinoid type-1 receptor antagonists novel Proliferators-Activated Receptor (PPAR) agonists and a systemic treatment designed to change the composition of the patient�s own HDL to a super HDL particle to prevent the rupture of vulnerable plaque by causing rapid regression of atherosclerosis are being studied. The purpose of this review is to examine key players in HDL metabolism and therapeutics that modulate these targets.