The treatment of lipid abnormalities generally has focused on low-density lipoprotein cholesterol (LDL-C) reduction based on extensive clinical trials and the National Cholesterol Education Program Adult Treatment Panel III guidelines. Unfortunately, it has become increasingly clear that a significant percentage of patients continue to have cardiovascular events despite being on LDL-C-lowering medications and having LDL-C levels below 100 mg/dL. Numerous epidemiologic studies have associated low high-density lipoprotein cholesterol (HDL-C) levels with increased risk of cardiovascular disease (CVD). Furthermore, recent data show that up to 55% of patients hospitalized for CVD have low HDL-C levels (<40 mg/dL) on admission, suggesting a possible target for further reducing CVD. Low HDL-C also is part of the atherogenic phenotype associated with obesity, glucose intolerance, and hypertension, termed the metabolic syndrome, and often is seen in patients with insulin resistance states. In general, the first line of therapy for increasing HDL-C in patients with levels below 40 mg/dL is lifestyle modification with smoking cessation, exercise, weight loss, and diet modifications. The pharmacologic treatment of isolated low HDL-C in patients without coronary disease is controversial but should be considered in those with a strong family history of CVD. In patients with coronary artery disease and isolated low HDL-C, statins remain the first-line therapy and should be instituted after lifestyle modifications, with the goal of increasing HDL-C above 40 mg/dL. If concomitant hypertriglyceridemia is present, a fibrate or niacin should be considered. Although statins do offer some HDL-C-raising properties, they tend to have modest effects. If treatment goals have not been achieved with either lifestyle changes or statin therapy, then the next agent of choice is niacin. Among the various HDL-C-raising therapies, niacin continues to be the most potent therapeutic option available. There are several novel HDL-C therapies in the research pipeline; however, only one class of medications is relatively close to clinical use, the cholesteryl ester transferase protein (CETP) inhibitors. Although one of the CETP inhibitors, torcetrapib, has received much negative attention from a large randomized trial showing increased mortality associated with its use, the overall class of therapeutic agents may still hold some benefit. Currently, two new CETP inhibitors without the off-target effects of torcetrapib are undergoing clinical research. Overall, the use of HDL-C-modifying agents likely will increase over the next decade.