High-density lipoprotein cholesterol (HDL-C) has been dubbed the good cholesterol because it is thought to reflect the ability of HDL particles to remove excess cholesterol molecules from peripheral cells (including those in atherosclerotic plaques) for return to the liver. Not surprisingly, then, HDL-C has frequently been assumed to be a biomarker of HDL function, consistent with the inverse relationship in observational studies between plasma levels of HDL-C and risk of coronary artery disease. Recently, Voight et al have challenged this assumption by showing that genetically elevated HDL-C did not protect against myocardial infarction. This finding has fueled a lively discussion in the lay, scientific, and medical press about the relationship between HDL-C and HDL function, and the potential effectiveness of various HDL-C raising strategies.