Epidemiologic and clinical trials show that elevated triglycerides and low levels of high-density lipoprotein cholesterol (HDL-C) are independent risk factors for coronary heart disease (CHD). However, adjustment for covariates frequently weakens or abolishes the predictive significance of triglycerides, whereas the evidence for HDL-C is more consistently strong. Data indicate that there is a 2% to 3% decrease in coronary risk for each 1 mg/dL increase in HDL-C, whereas the benefit of triglyceride lowering appears to occur largely in patients with the highest baseline levels. The 2001 National Cholesterol Education Program Adult Treatment Panel III (ATP III) guidelines for detecting and treating high blood cholesterol reflect our improved understanding of triglycerides and HDL as CHD risk factors. However, the guidelines place more emphasis on lowering triglycerides than on raising HDL-C by identifying non-HDL-C (ie, low-density lipoprotein cholesterol [LDL-C] + very-low-density lipoprotein cholesterol [VLDL-C]) as a secondary target of therapy. In clinical practice, VLDL-C is the most readily available measure of atherogenic triglyceride-rich remnant lipoproteins. On the basis of the available epidemiologic and clinical evidence, refinement of the NCEP guidelines to include more emphasis on raising HDL-C levels should be considered. Novel drugs are being developed that have the potential to increase HDL-C concentrations and/or improve the functionality of HDL. (Am Heart J 2002;144:S33-42.)