The clinical importance of low serum levels of high-density lipoprotein (HDL) cholesterol is often under-recognized and underappreciated as a risk factor for premature atherosclerosis as well as for cardiovascular morbidity and mortality. Low serum levels of HDL are frequently encountered, especially in patients who are obese or have the metabolic syndrome. In prospective epidemiologic studies, every 1-mg/dL increase in HDL is associated with a 2% to 3% decrease in coronary artery disease risk, independent of low-density lipoprotein (LDL) cholesterol and triglyceride (TG) levels. The primary mechanism for this protective effect is believed to be reverse cholesterol transport, but several other anti-inflammatory, antithrombotic, and antiproliferative functions for HDL have also been identified. In recognition of these antiatherogenic effects, recent guidelines have increased the threshold for defining low levels of HDL for both men and women. The first step in achieving these revised targets is therapeutic lifestyle changes. When these measures are inadequate, pharmacotherapy specific to the patient's lipid profile should be instituted. Niacin therapy, currently the most effective means for raising HDL levels, should be initiated in patients with isolated low HDL (HDL <40 mg/dL, LDL and non-HDL at or below National Cholesterol Education Program (NCEP) targets based on global cardiovascular risk evaluation). Patients who have both low HDL and elevated LDL should receive a statin or statin-niacin combination therapy, and patients with concomitant low HDL and elevated TGs should receive a fibrate initially, with a statin, niacin, or ezetimibe added thereafter as needed to help attain NCEP lipoprotein targets.