A low level of high-density lipoprotein cholesterol (HDL-C) is an important risk factor for cardiovascular disease. Epidemiological and clinical studies provide evidence that HDL-C levels are linked to rates of coronary events. The cardioprotective effects of HDL-C have been attributed to its role in reverse cholesterol transport, its effects on endothelial cells, and its antioxidant activity. Although some clinical trials suggest a benefit of raising HDL-C to reduce risk, further studies are needed, and HDL-C is still not considered a primary target of therapy in the National Cholesterol Education Program guidelines. However, HDL-C should be considered as part of the patient’s overall profile of established risk factors in determining treatment strategies.