Epidemiologic studies have established that a low concentration of plasma high-density lipoprotein (HDL) cholesterol is an independent risk factor for coronary heart disease (CHD). In the United States, a low HDL cholesterol concentration is the most prevalent lipid abnormality observed in men with known CHD. Despite this fact, surprisingly few clinical trials have been designed to investigate the effects of pharmacologic agents on HDL cholesterol-raising and CHD risk in large populations, perhaps due, in part, to the lack of available drugs having significant HDL cholesterol-raising potential. The purpose of this report is to review recent primary and secondary prevention trials that have explored the relationships between drug therapy, HDL cholesterol concentration, and CHD events or progression. Emphasis will be placed on the results of the Veterans Affairs High-Density Lipoprotein Trial, a study that was specifically designed to test the hypothesis that HDL cholesterol-raising with gemfibrozil would reduce CHD morbidity and mortality in patients with CHD whose primary lipid abnormality was a low level of HDL cholesterol.