Niacin is the most effective medication in current clinical use for increasing high-density lipoprotein (HDL) cholesterol. It has the broadest effect on the lipid profile, reducing all atherogenic apolipoprotein (apo) B and increasing all antiatherogenic apo AI-containing lipoproteins, resulting in significant reduction in atherosclerotic complications and total mortality in trials. Recent research indicates novel major target sites of action in the liver to 1) directly inhibit diacylglycerol acyltransferase 2 (DGAT2), explaining its effect on triglycerides and apo B lipoproteins, and 2) inhibit the HDL apo AI catabolism pathway, resulting in higher HDL levels. Such information may lead to new drug discovery and supply the rationale for combination with other lipid regulators that are known to have different mechanisms of action. Trial evidence shows that niacin is not only safe to use in persons with diabetes, but that its combination with 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG CoA) reductase inhibitors (statins) is also safe and effective. Recently, a new formulation of niacin has made it easier to tolerate and administer. Clinical trials are needed to determine whether niacin in combination with other lipid-modulating agents decreases the risk of cardiovascular events beyond the approximately 30% that has been noted with monotherapy.