There is abundant epidemiologic evidence to support the independent, inverse relationship between low levels of high-density lipoprotein cholesterol (HDL-C) and incident cardiovascular (CV) risk, the clinical importance of which is underscored by the high prevalence of low HDL-C in populations with coronary heart disease (CHD), with or without elevated levels of low-density lipoprotein cholesterol (LDL-C). The National Cholesterol Education Program recommended that optimal treatment for high-risk patients includes both lowering LDL-C and non-HDL-C to risk stratified levels and raising HDL-C when it is <40 mg/dL, although no target level for the latter lipoprotein was suggested. Niacin is the most powerful agent currently available for raising low levels of HDL-C. It also induces significant reductions in triglycerides, lipoprotein(a), and LDL-C levels while also favorably altering LDL particle size and number. In the Coronary Drug Project, niacin treatment was associated with significant reductions in CV events and long-term mortality, similar to the reductions seen in the statin monotherapy trials. In combination trials, niacin plus a statin or bile acid sequestrant produces additive reductions in CHD morbidity and mortality and promotes regression of coronary atherosclerosis. Recently, 2 clinical outcome trials (Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides and Impact on Global Health Outcomes [AIM-HIGH] and Second Heart Protection Study [HPS-2 THRIVE]) failed to show a reduction in CV events in patients treated to optimally low levels of LDL-C. Despite favorable effects on HDL-C and triglycerides, these studies did not demonstrate incremental clinical benefit with niacin when added to simvastatin, although notable limitations were identified in each of these trials. Thus, there is insufficient evidence from clinical trials to recommend HDL-targeted therapy for additional event reduction at the present time. However, niacin should continue to be used as an adjuvant therapy for reducing atherogenic lipoprotein burden in patients who have not reached their risk stratified LDL-C and non-HDL-C targets.