Numerous studies have shown that levels of high-density lipoprotein (HDL) cholesterol are inversely related to coronary artery disease risk. The HDL subfractions, however, seem to differ in their capacity to confer protection, with the large HDL2 subfraction appearing to be more important than the small HDL3 subfraction. Lipid-modifying drugs differ in their HDL-raising efficacy, and they also differ in how they affect HDL subfractions. Clinical trials show that raising total HDL cholesterol improves clinical and angiographic outcomes. It remains to be determined, however, whether a shift in distribution of HDL particles provides greater benefit than just an increase in total HDL.