There is strong epidemiological evidence that HDL-cholesterol (HDL-C) is an independent cardiovascular risk factor. A low HDL-C is a common finding in the general population, and is a feature of metabolic syndrome, the prevalence of which is increasing globally. The importance of HDL-C as a coronary risk factor is generally accepted, and has been incorporated into most of the commonly applied risk engines. There are several causes of a low HDL-C, including rare genetic abnormalities, and more common conditions associated with lifestyle and drug therapy. Not all of these are associated with an increased risk of coronary disease. A better understanding of HDL metabolism and the mechanisms by which it may exert its protective effects has revealed why this may be the case. New therapeutic targets have also been identified that may allow HDL-C to be raised in patients with low levels. However, good clinical endpoint studies are still required to enable the setting of absolute target values for HDL-C in patients at high cardiovascular risk.