Owing to many potentially anti-atherogenic functions and the inverse correlation of high-density lipoprotein (HDL)-cholesterol (C) plasma levels with cardiovascular risk, HDLs have evolved as an attractive target for the prevention and therapy of coronary heart disease. Previously, the failure of torcetrapib, the frequent confounding of low HDL-C with other pro-atherogenic conditions, as well as inconsistent data from patients and animal models with genetic HDL dyslipidemias, left in doubt the suitability of HDL-C as a target for anti-atherogenic therapy. However, HDL-C is an integrative but nonfunctional measure of particle size and number. Therefore, biomarkers reflecting the functionality of HDL particles are needed to assess and monitor the cardiovascular risk exerted by disturbances and treatments of HDL metabolism, respectively. Moreover, the discovery of novel therapeutics that improve HDL metabolism, mimic HDL function, or cure the regulatory network underlying dyslipidemias and dysfunctions of HDL should be a major aim of atherosclerosis research.