Atherosclerosis is the leading cause of heart disease, contributing to hundreds of thousands of deaths annually. The use of long-term antilipid therapy has decreased low-density lipoprotein as a target, but high-density lipoprotein (HDL) has many properties which can protect against the formation of atherosclerotic plaque and decrease plaque burden. Numerous studies have shown an inverse correlation with HDL level and the future risk of heart disease. HDL has the unique property of playing a key role in reverse cholesterol transport, essentially bringing cholesterol from the periphery back to the liver for excretion in bile. In addition, HDL has many anti-inflammatory and vasoprotective properties. Recently, the idea of using HDL as a target of therapy has been met with great interest. Although oral medications have not shown promise, newly developed HDL infusions are currently being tested in clinical trials to determine their effect on the amount of plaque, the composition of the plaque, and the general state of inflammation. HDL infusions achieve stable levels rapidly in the plasma, making them most suitable in the post-acute coronary syndrome stage when most ischemic events are likely to recur. These infusion therapies have repeatedly demonstrated viability and reproducibility in increasing the amount of circulating HDL, decreasing the plaque burden, and decreasing markers of inflammation in plasma. However, none thus far have demonstrated a mortality benefit, possibly reflecting the complexity of the relationship among HDL, inflammation, and atherosclerosis. This remains a viable and promising avenue for continued research.